Laser-based method and system for selectively processing target tissue material in a patient and optical catheter assembly for use therein

ABSTRACT

A laser-based method and system for selectively processing target tissue material in a patient and optical catheter assembly for use therein are provided. The system includes a laser subsystem for generating an output laser beam. The system further includes a catheter assembly including at least one optical fiber having a proximal end coupled to the laser subsystem for guiding the output laser beam along a propagation path. The beam has optical and temporal properties and a predetermined selected wavelength. The catheter assembly is sized to extend through an opening in a first part of the patient and to a tissue material processing site within the patient. The catheter assembly includes a beam delivery and focusing subsystem which has an adjustable focal distance and disposed in the propagation path and that accepts the output laser beam and adjustably positions the beam into at least one focused spot on the target tissue material disposed within a second part of the patient at the site based on distance to the target tissue material from a predetermined point on the propagation path at the site for a duration sufficient to allow laser energy to be absorbed by the target tissue material and converted to heat to produce a desired physical change in the target tissue material without causing undesirable changes to adjacent non-target material disposed within the second part of the patient. The target tissue material is characterized by an absorptive coefficient. The predetermined wavelength is selected to achieve a penetration depth into the second part of the patient of approximately one millimeter or more.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. national phase of PCTAppln. No. PCT/US2010/062467 filed Dec. 30, 2010, which claims thebenefit of U.S. provisional patent application Ser. Nos. 61/335,456,61/335,455, and 61/335,440 all filed Jan. 7, 2010, the disclosures ofwhich are incorporated in their entirety by reference herein.

TECHNICAL FIELD OF THE INVENTION

This invention relates in general to lasers and light sources forhealthcare, medical, or bio-technology applications, and moreparticularly to systems, methods and optical catheters fortherapeutically, selectively damaging or processing biological materialassociated with certain tissue types.

Overview

Many of the lasers that are used in healthcare, medical orbio-technology applications operated on the basis of absorption of thelight in water. However, since water pervades most biological tissue,the medical lasers tend not to be selective to a particular tissue type.During medical procedures using such non-selective lasers, there can beadditional risk and complications from unwanted collateral damage. Also,for laser wavelengths that are significantly absorbed by water, thelight may not penetrate very far into the tissue. Consequently, laserstend to treat only the surface of the tissue exposed to the light.Therefore, there exists a need for lasers and procedures based on lightsources or lasers that can be selective and that can penetrate deeperinto tissue.

Mid-infrared lasers, such as lasers that operate between approximately 1and 10 microns, preferably between 1.2 and 4.5 microns, can beimplemented that operate near absorption peaks of various tissues, suchas adipose (e.g., fat, cholesterol, lipids), collagen and elastin.Moreover, the wavelength of the lasers can be selected to minimize waterabsorption and scattering through tissue. Thus, mid-infrared laserstuned to optical absorption in particular tissue constituents can beused in one embodiment for selective damage in therapeutic procedures.In another embodiment, the optical absorption or reflection spectroscopycan be used as a diagnostic technique to differentiate between differenttissue types. Moreover, by operating at mid-infrared wavelengths withless water absorption and tissue scattering, the penetration depth forthe light can be increased to several millimeters, as an example. Thesefeatures of mid-infrared light can be beneficial in a number of medicalfields, including but not limited to ophthalmology, dermatology,cardiology and neurology as well as treatment of type 2 diabetes andother ailments associated with obesity.

The following U.S. patent references are related to at least one exampleembodiment of the present invention: U.S. Pat. Nos. 5,618,284;5,779,696, 6,159,205; 6,251,103; 6,605,080; 6,986,764; 7,060,061;7,633,673; 2008/0015557; 2009/0028193; and 2009/0054879.

SUMMARY OF EXAMPLE EMBODIMENTS

In a method embodiment, a laser-based method of selectively processingtarget tissue material in a patient is provided. The method includesgenerating and guiding an output laser beam along a propagation path.The beam has optical and temporal properties and a predeterminedselected wavelength. The path extends through an opening in a first partof the patient and to a tissue material processing site within thepatient. The method further includes delivering and adjustably focusingthe output laser beam into at least one focused spot on the targettissue material disposed within a second part of the patient at the sitebased on distance to the target tissue material from a predeterminedpoint on the propagation path at the site for a duration sufficient toallow laser energy to be absorbed by the target tissue material andconverted to heat to produce a desired physical change in the targettissue material without causing undesirable changes to adjacentnon-target material disposed within the second part of the patient. Thetarget tissue material is characterized by an absorptive coefficient.The predetermined wavelength is based on the absorptive coefficient ofthe target tissue material. The adjacent non-target material has anabsorptive coefficient different from the absorptive coefficient of thetarget tissue material at the predetermined wavelength and thepredetermined wavelength is selected to achieve a penetration depth intothe second part of the patient of approximately one millimeter or more.

In a system embodiment, a system for selectively processing targettissue material in a patient is provided. The system includes a lasersubsystem for generating an output laser beam. The system furtherincludes a catheter assembly including at least one optical fiber havinga proximal end coupled to the laser subsystem for guiding the outputlaser beam along a propagation path. The beam has optical and temporalproperties and a predetermined selected wavelength. The catheterassembly is sized to extend through an opening in a first part of thepatient and to a tissue material processing site within the patient. Thecatheter assembly further includes a beam delivery and focusingsubsystem which has an adjustable focal distance and disposed in thepropagation path and that accepts the output laser beam and adjustablypositions the beam into at least one focused spot on the target tissuematerial disposed within a second part of the patient at the site basedon distance to the target tissue material from a predetermined point onthe propagation path at the site for a duration sufficient to allowlaser energy to be absorbed by the target tissue material and convertedto heat to produce a desired physical change in the target tissuematerial without causing undesirable changes to adjacent non-targetmaterial disposed within the second part of the patient. The targettissue material is characterized by an absorptive coefficient. Thepredetermined wavelength is selected to achieve a penetration depth intothe second part of the patient of approximately one millimeter or more.

In an optical catheter assembly embodiment, an optical catheter assemblyfor use in a system for selectively processing target tissue material ina patient is provided. The assembly includes an elongated flexiblehousing. The assembly further includes an optical fiber disposed in thehousing for guiding an output laser beam along a propagation path. Thebeam has optical and temporal properties and a predetermined selectedwavelength. The housing is sized to extend through an opening in a firstpart of the patient and to a tissue material processing site within thepatient. The assembly still further includes a beam delivery andfocusing subsystem which has an adjustable focal distance disposed inthe propagation path and accepts the output laser beam and adjustablypositions the beam into at least one focused spot on the target tissuematerial disposed within a second part of the patient at the site basedon distance to the target tissue material from a predetermined point onthe propagation path at the site for a duration sufficient to allowlaser energy to be absorbed by the target tissue material and convertedto heat to produce a desired physical change in the target tissuematerial without causing undesirable changes to adjacent non-targetmaterial disposed within the second part of the patient. The targettissue material is characterized by an absorptive coefficient. Thepredetermined wavelength is based on the absorptive coefficient of thetarget tissue material. The adjacent non-target material has anabsorptive coefficient different from the absorptive coefficient of thetarget tissue material at the predetermined wavelength.

Depending on the specific features implemented, particular embodimentsof the present invention may exhibit some, none, or all of the followingtechnical advantages. Various embodiments may be capable of penetrationdeep into tissue. Some embodiments may be capable of penetrating severalmillimeters into such tissue.

Other technical advantages will be readily apparent to one skilled inthe art from the following figures, description and claims. Moreover,while specific advantages have been enumerated, various embodiments mayinclude all, some or none of the enumerated advantages.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention, and forfurther features and advantages thereof, reference is now made to thefollowing description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 illustrates the optical absorbance spectrum for four types ofcollagen in the mid-infrared wavelength range between 1200 nm (1.2microns) and 2400 nm (2.4 microns); the upper left curve corresponds tothe absorbance for collagen I, the upper right curve corresponds to theabsorbance for collagen II, the lower left curve corresponds to theabsorbance for collagen III, and the lower right curve corresponds tothe absorbance for collagen IV;

FIG. 2 illustrates the optical absorbance of elastin in the mid-infraredwavelength range between approximately 1200 nm and 2400 nm;

FIG. 3 overlaps the absorption coefficient of adipose tissue withcollagen I and elastin; vertical lines are also drawn to highlight thewavelengths near 1210 nm and 1720 nm; the adipose absorption coefficientis shown on a calibrated scale, while the collagen and elastin are inarbitrary units;

FIG. 4 illustrates separately the exemplary water absorption andscattering loss; the top of FIG. 4 is the reduced scattering coefficientthrough tissue such as dermis, while the bottom of FIG. 4 is theabsorption coefficient of water;

FIG. 5 illustrates exemplary the combined water absorption andscattering loss curves; FIG. 5 adds the two curves of FIG. 4 to providethe resulting water absorption and scattering loss;

FIG. 6 illustrates the overlap of the absorption coefficients for water,adipose, collagen and elastin; vertical lines are also drawn tohighlight the wavelengths near 1210 nm and 1720 nm; the adipose andwater absorption coefficients are shown on a calibrated scale, while thecollagen and elastin are in arbitrary units;

FIG. 7 illustrates the overlap of the absorption coefficients for waterand tissue scattering, adipose, collagen and elastin; vertical lines arealso drawn to highlight the wavelengths near 1210 nm and 1720 nm; theadipose and water absorption coefficients as well as the scattering lossare shown on a calibrated scale, while the collagen and elastin are inarbitrary units;

FIG. 8 illustrates a block diagram of one embodiment of a mid-infraredfiber laser operating near 1720 nm;

FIG. 9 shows details of one specific example of a mid-infrared fiberlaser operating at approximately 1708 nm; the top part of the figureillustrates one embodiment of the pump fiber laser, and the bottom partof the figure illustrates one embodiment of the cascaded Ramanoscillator or cascaded Raman wavelength shifter;

FIG. 10A illustrates a block diagram yet another embodiment of amid-infrared fiber laser operating near 1210 nm;

FIG. 10B shows details of one specific example of a mid-infrared fiberlaser operating at approximately 1212 nm; the top part of the figureillustrates one embodiment of the pump fiber laser, and the bottom partof the figure illustrates one embodiment of the cascaded Ramanoscillator or cascaded Raman wavelength shifter;

FIG. 11A illustrates a block diagram of one embodiment of a mid-infraredsuper-continuum fiber laser;

FIG. 11B shows a particular example of a mid-infrared super-continuumlaser that can generate relatively high powers;

FIG. 12A illustrates details of different exemplary super-continuumlasers; the top of the figure provides details of an SC source that canprovide light from approximately 1400 nm to 1800 nm or broader, whilethe bottom of the figure provides details of an SC source that canprovide light from about 1900 nm to 2500 nm or broader;

FIG. 12B illustrates one embodiment of a thulium-doped fiber laseroperating near a center wavelength around 1720 to 1750 nm or longer; thetop left curve shows exemplary absorption bands for thulium in fusedsilica fiber, and the top right curve shows exemplary absorption andemission bands for thulium in the wavelength range between approximately1400 and 2100 nm; the bottom configuration illustrates one embodiment ofthe thulium-doped fiber laser operating in the mid-infrared wavelengthrange;

FIG. 13 illustrates experimental results for the depth of damageobtained in an in-vitro human skin sample plotted as a function of laserfluence at about 1708 nm incident on the skin sample;

FIG. 14 illustrates a cross-sectional view of the human eye; the rightside of the diagram is an enlarged view of the various layers comprisingthe cornea;

FIG. 15 is a schematic of some of the main layers of the human skin; forexample, the dermis comprises collagen and elastin;

FIG. 16 shows an exemplary sketch of human skin and the definitions of askin line, skin wrinkle and skin fold;

FIG. 17 provides a schematic of a normal artery (left) and an arterywith atherosclerotic plaque build-up on the inside walls (right);

FIG. 18 illustrates exemplary measured optical spectra of constituentsin atherosclerotic plaque and normal artery walls between thewavelengths of approximately 2600 nm and 3800 nm; some of theconstituents of normal artery include: (a) endothelium cell and (b)smooth muscle cell; some of the constituents of atherosclerotic plaqueinclude: (c) macrophage, (d) fat tissue, and (e) foam cells;

FIG. 19 illustrates the optical absorption of egg yolk and endothelialcells; for example, by using light in the wavelength range near 3300 to3600 nm, the egg yolk can be selectively damaged compared withendothelial cells;

FIG. 20 illustrates an exemplary laparoscopic device for use forintroducing light into the abdominal region; in one embodiment, such alaparoscopic device could be used to remove visceral adipose tissue;

FIG. 21 shows a schematic for an exemplary probe or catheter that can beused for inserting into an artery;

FIG. 22 illustrates the transmission (one minus the absorbance) throughfatty tissue, aorta and heart muscle or myocardium without endo- orepi-cardium; the longer arrows indicate some of the water absorptionbands, while the shorter arrows indicate some of the approximateabsorption bands in fatty tissue;

FIG. 23 illustrates near-infrared spectroscopy data for diagnosingcolorectal or pancreatic cancer; the top left hand side showsnear-infrared spectra for normal and cancerous pancreas and colorectaltissue, while the bottom left hand side enhances the changes bydifferentiating the reflectance to show the missing lipid lines; theright hand side enlarges the data in the wavelength range betweenapproximately 1670 and 1790 nm, which illustrates the contrast betweennormal and cancerous colorectal tissue;

FIG. 24 is a sectional view of a renal artery;

FIG. 25 is a schematic view of a parabolic mirror with a reflectivesurface having a radius of curvature;

FIG. 26 a is a graph of focal distance versus fiber distance for aparticular radius of mirror curvature;

FIG. 26 b is a graph of RMS spot radius versus focal distance for thecurved mirror;

FIG. 27 are spot diagrams for corresponding different focal distancesnoted in FIG. 26 a;

FIG. 28 a is a side schematic view of an adaptive curved mirrorcomprising a plurality of controlled MEMS micro-mirrors;

FIG. 28 b is a side schematic view of an adaptive curved mirror having adeformable reflective surface;

FIG. 29 a is a graph of focal distance versus radius of mirrorcurvature;

FIG. 29 b is a graph of geometric beam radius versus focal distance;

FIG. 30 is a side schematic view of a flat mirror with an associatedfocusing lens;

FIG. 31 a is a graph of focal distance versus radius of lens curvature;

FIG. 31 b is a graph of beam radius at focus versus radius of lenscurvature;

FIG. 32 is a graph of focal distance versus fiber distance from abending mirror;

FIG. 33 are spot diagrams from corresponding different focal distancesnoted in FIG. 32;

FIG. 34 is a side schematic view, partially broken away, of acylindrically symmetric catheter probe between the side walls of asample or artery;

FIG. 35 is a side schematic view, partially broken away, of a singlelaser output coupled to four fibers which are fed into a catheter;

FIG. 36 is a side schematic view, partially broken away and incross-section, of a catheter device having an inflated balloon whichengages the side walls of an artery;

FIG. 37 a is a view similar to the view of FIG. 36 with a balloon headof the device deflated;

FIG. 37 b is a view similar to the view of FIG. 37 a with the balloonhead inflated;

FIG. 38 is a side schematic view, partially broken away and incross-section, of another balloon-type catheter;

FIG. 39 a is a side schematic view, partially broken away, of a catheterhaving fluid cooling for a curved mirror;

FIG. 39 b is a side schematic view, partially broken away, of a catheterhaving a tapered fiber;

FIG. 39 c is a side schematic view, partially broken away, of a catheterhaving a multimode fiber;

FIG. 40 is a side schematic view, partially broken away, of a catheterwith a grin lens or refractive element-tipped fiber;

FIG. 41 is a side schematic view of a parabolic mirror with anassociated focusing mirror of a multi-element optical subsystem;

FIG. 42 is a graph of focal distance versus fiber distance for theconfiguration of FIG. 41;

FIG. 43 is a side schematic view of a flat mirror with a pair of lensesof a multi-element optical subsystem;

FIG. 44 a is a graph of focal distance versus distance between a firstlens and mirror of FIG. 43; and

FIG. 44 b is a graph of focal distance versus distance between the pairof lenses of FIG. 43.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

Mid-infrared light sources can be used for diagnostics and therapeuticsin a number of medical applications. For example, broadband lightsources can advantageously be used for diagnostics, while narrower bandlight sources can advantageously be used for therapeutics. In oneembodiment, selective absorption or damage can be achieved by choosingthe laser wavelength to lie approximately at an absorption peak ofparticular tissue types. Also, by using mid-infrared wavelengths thatminimize water absorption peaks and longer wavelengths that have lowertissue scattering, larger penetration depths into the biological tissuecan be obtained. As an example, tissues such as adipose, collagen andelastin have absorption peaks in the mid-infrared wavelengths. In thisdisclosure, we define mid-infrared wavelengths as wavelengths in therange of 1 to 10 microns, more preferably wavelengths between about 1.2and 4.5 microns.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. In this disclosure, the term “damage” refers to affecting atissue or sample so as to render the tissue or sample inoperable. Forinstance, if a particular tissue normally emits certain signalingchemicals, then by “damaging” the tissue is meant that the tissuereduces or no longer emits that certain signaling chemical. The term“damage” and or “damaged” may include ablation, melting, charring,killing, or simply incapacitating the chemical emissions from theparticular tissue or sample. In one embodiment, histology orhistochemical analysis may be used to inspect if a tissue or sample hasbeen damaged.

As used throughout this disclosure, the term “spectroscopy” means that atissue or sample is inspected by comparing different features, such aswavelength (or frequency), spatial location, transmission, absorption,reflectivity, scattering, refractive index, or opacity. In oneembodiment, “spectroscopy” may mean that the wavelength of the lightsource is varied, and the transmission, absorption or reflectivity ofthe tissue or sample is measured as a function of wavelength. In anotherembodiment, “spectroscopy” may mean that the wavelength dependence ofthe transmission, absorption or reflectivity is compared betweendifferent spatial locations on a tissue or sample. As an illustration,the “spectroscopy” may be performed by varying the wavelength of thelight source, or by using a broadband light source and analyzing thesignal using a spectrometer, wavemeter, or optical spectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium or thulium. Inone embodiment, the “pump laser” may be a fiber laser, a solid statelaser, a laser involving a nonlinear crystal, an optical parametricoscillator, a semiconductor laser, or a plurality of semiconductorlasers that may be multiplexed together. In another embodiment, the“pump laser” may be coupled to the gain medium by using a fiber coupler,a dichroic mirror, a multiplexer, a wavelength division multiplexer, agrating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth or at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, the Ramaneffect, modulational instability, and self-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

As used throughout this document, the term “near 1720 nm” refers to oneor more wavelengths of light with a wavelength value anywhere betweenapproximately 1680 nm and 1760 nm. In a preferred embodiment, the term“near 1720 nm” refers to one or more wavelengths of light with awavelength value anywhere between approximately 1700 nm and 1740 nm.Similarly, as used throughout this document, the term “near 1210 nm”refers to one or wavelengths of light with a wavelength value anywherebetween approximately 1170 nm and 1250 nm. In a preferred embodiment,the term “near 1210 nm” refers to one or wavelengths of light with awavelength value anywhere between approximately 1190 nm and 1230 nm.

To better understand the diagnostic and therapeutic applications, theoptical spectra of a number of tissue types or tissue constituents arefirst reviewed.

Optical Spectra for Different Tissue Constituents

FIG. 1 illustrates the optical absorbance for different types ofcollagen 100 in the mid-infrared wavelength range between approximately1200 and 2400 nm, which also corresponds to 1.2 to 2.4 microns. Theupper left curve 101 is exemplary the absorption spectrum for collagenI, which can be one of the main constituents in the dermis of the skinas well as the cornea of the eye. Curve 102 corresponds to theabsorbance for collagen II, curve 103 corresponds to the absorbance forcollagen III, and curve 104 to the absorbance for collagen IV. Incardiology, the aorta comprises mostly type I and type III collagen. Tobe specific when discussing collagen spectra in this disclosure, thespectra for collagen I 101 will be used, unless stated otherwise. In theparticular case of collagen I, there are local absorbance peaks near1210 nm and 1720 nm. As further discussed below, these wavelengthwindows can be particularly interesting because of lower waterabsorption at these wavelengths.

FIG. 2 illustrates the optical absorbance of elastin 201 in themid-infrared wavelength range between approximately 1200 nm and 2400 nm.Elastin can be one of the main constituents of the dermis, and it givesthe skin some of the elasticity and springy properties. Elastin can havea unique optical spectrum 200 that differentiates it from collagens 100.Despite the difference in absorbance shape from collagen I, there isalso a local absorbance peak near 1720 nm.

FIG. 3 better illustrates similarities and differences in themid-infrared spectra for collagen I 302 and elastin 303. The twoabsorbance curves are in arbitrary units, so the shapes and peaks inabsorption can be compared, but the amplitudes of the absorptioncoefficient are arbitrary. Also shown are vertical lines demarking thewavelengths of approximately 1210 nm 304 and 1720 nm 305. Near 1720 nm,both the elastin and collagen have local absorption peaks that nearlycoincide in wavelength. Whereas collagen has another local absorptionpeak near 1210 nm, the elastin local peak is about 25 nm shorter atapproximately 1185 nm.

Another tissue type of interest is adipose, which includes fatty tissueand acids, lipids, and cholesterol. FIG. 3 overlaps the absorptioncoefficient of adipose tissue 301 with collagen 302 and elastin 303. Itcan be noted that adipose, collagen and elastin all show a localabsorption peak near 1720 nm. Also, adipose and collagen have a localabsorption peak near 1210 nm, although elastin has the local absorptionpeak closer to 1185 nm.

Blood is prevalent throughout the body, and it may be desirable to avoidabsorption in blood to achieve selective absorption in certain tissuetypes. Most of the absorption in blood can be in the visible andultraviolet wavelengths, and the absorption in hemoglobin isapproximately transparent by approximately 1200 nm. Beyond thiswavelength range in the mid-infrared, the absorption coefficient ofblood closely resembles the absorption coefficient of water.

In general, to understand the propagation through and penetration intobiological tissue, water absorption 402 and scattering loss 401 shouldbe considered. FIG. 4 illustrates these two contributions to lightattenuation separately, and then FIG. 5 adds the two curves to providethe resulting total absorption and reduced scattering coefficient 501.The bottom of FIG. 4 plots the absorption coefficient of water 402 inthe mid-infrared wavelength range between 1200 and 1900 nm, and localpeaks in water absorption are seen exemplary near 1450 nm and 1940 nm.In addition, the top of FIG. 4 plots the reduced scattering coefficient401 as measured propagating through the dermis. In accordance withscattering theory, the scattering loss follows an approximate scalinglaw of the inverse of the square of the wavelength. Therefore, oneadvantage of using longer wavelengths can be that the scattering loss isreduced. FIG. 5, which is the sum of the two curves in FIG. 4, showsthat there are relative minima in the total absorption and scattering501 near 1210 nm (approximately 6.8 cm⁻¹) and 1720 nm (approximately8.25 cm⁻¹).

FIG. 6 illustrates the overlap of the absorption coefficients for water601, adipose 602, collagen 603 and elastin 604. Note that the absorptioncurves for water 601 and adipose 602 are calibrated, whereas theabsorption curves for collagen 603 and elastin 604 are in arbitraryunits. Also shown are vertical lines demarcating the wavelengths near1210 nm 605 and 1720 nm 606. As an example, the absorption coefficientfor adipose 602 exceeds the water absorption 601 in the wavelengthwindows near 1210 nm and 1720 nm. However, near 1210 nm there is a localmaximum in water absorption, while near 1720 nm the wavelength is in thevicinity of a minimum in water absorption. There are peaks in waterabsorption near 970 nm, 1190 nm, 1450 nm and 1940 nm, and there is alsoa large water peak near 3000 nm. Also, in general, the water absorptionincreases with increasing wavelength. With the increasing absorptionbeyond about 2000 nm, it may be difficult to achieve deeper penetrationinto biological tissue in the mid-infrared wavelengths beyond 2000 nm.

Although FIG. 6 can be useful for determining the material in whichlight of a certain mid-infrared wavelength will be absorbed, todetermine the penetration depth of the light of a certain wavelength mayalso require the addition of scattering loss to the curves. For example,FIG. 7 modifies the figure by also including the scattering loss curveto the water absorption 701 (i.e., uses FIG. 5 rather than just thewater absorption in the bottom of FIG. 4). Since the scattering loss canbe significantly higher at shorter wavelengths, the comparison ofadipose absorption 702 to loss propagating through water and tissuescattering 701 can be altered, particularly for wavelengths belowapproximately 1400 nm. In one embodiment, near the wavelength of 1720 nm(vertical line 706 shown in FIG. 7), the adipose absorption 702 canstill be higher than the water plus scattering loss 701. For tissue thatcontains adipose, collagen and elastin, such as the dermis of the skin,the total absorption can exceed the light energy lost to waterabsorption and light scattering at 1720 nm. On the other hand, at 1210nm the adipose absorption 702 can be considerably lower than the waterplus scattering loss 701, particularly since the scattering loss can bedominant at these shorter wavelengths. As in FIG. 6, in FIG. 7 theabsorption curves for water, scattering and adipose are calibrated,whereas the absorption curves for collagen and elastin are in arbitraryunits.

One further consideration in choosing the laser wavelength is known asthe “eye safe” window. In particular, wavelengths in the eye safe windowmay not transmit down to the retina of the eye, and therefore, thesewavelengths may be less likely to create permanent eye damage. Themid-infrared wavelengths have the potential to be dangerous, because theeye cannot see the wavelengths (as it can in the visible), yet they canpenetrate and cause damage to the eye. Even if a practitioner is notlooking directly at the laser beam, the practitioner's eyes may receivestray light from a reflection or scattering some surface. Hence, it canalways be a good practice to use eye protection when working aroundlasers.

Since wavelengths longer than about 1400 nm are substantially nottransmitted to the retina or substantially absorbed in the retina, thiswavelength range is known as the eye safe window. For wavelengths longerthan 1400 nm, in general only the cornea of the eye may receive orabsorb the light radiation. Thus, for example, wavelengths near 1210 nmdo not fall in the eye safe window, while wavelengths near 1720 nm arewithin the eye safe window. Although the pump lasers or intermediateorders in the laser system may not fall within the eye safe wavelengthrange, these wavelengths may be substantially blocked or filtered withinthe laser unit. Consequently, to achieve an eye safe laser evenoperating at a wavelength such as 1720 nm, the residual intermediate andpump wavelengths should be substantially filtered before the fiber orfree space output.

Mid-Infrared Fiber Lasers

As an example, FIGS. 6 and 7 illustrate that there could be novelselective damage to tissue constituents or spectroscopy to detectparticular tissue constituents, which could lead to novel medicaldiagnostics or therapeutics. In one embodiment, relatively narrow bandlasers can be constructed near 1210 nm or 1720 nm by using cascadedRaman oscillators. These lasers could be beneficial for therapeuticmedical procedures and can generate relatively high spectral density atwavelengths of interest. In another embodiment, super-continuum (SC)light sources or lasers can be implemented that can be broadband in themid-infrared wavelength range and that could be beneficial fordiagnostic medical procedures. The broadband light can be helpful forprocedures based on spectroscopy, which, for example, can rely on thewavelength characteristics of different constituents to identify theconstituents' presence through an algorithm such as spectralfingerprinting. Below some examples of cascaded Raman oscillators andsuper-continuum light sources are provided, along with examples of fiberlasers based on single-mode or double-clad fibers. These are exemplarymid-infrared fiber lasers, but other mid-infrared lasers, such as solidstate lasers or semiconductor lasers, can also be used consistent withthis disclosure.

In one embodiment, a mid-infrared laser can be constructed by using apump fiber laser to generate a pump signal, and then to wavelength shiftthe pump signal to a longer wavelength using a cascaded Ramanoscillator. In a preferred embodiment, the cascaded Raman oscillator canbe a fiber surrounded by a plurality of gratings. As an example, thefiber laser can be a ring laser cavity or a linear laser cavity. Forexample, a ring laser cavity can be made with couplers surrounding again fiber. In another example, a linear laser cavity can comprise oneor more optical gratings surrounding a gain fiber. In a preferredembodiment, the gain fiber can be a doped fiber, such as aytterbium-doped fiber, an erbium-doped fiber, an erbium/ytterbium dopedfiber, or a thulium doped fiber. Also, higher powers can be generated byusing a gain fiber that is a cladding pumped fiber or a double cladfiber. Alternatively, the gain fiber could potentially be a photoniccrystal fiber. Although particular examples are provided for doping andfiber types, different combinations or alternatives can be usedconsistent with this disclosure.

FIG. 8 illustrates a block diagram of one embodiment of a mid-infraredfiber laser 800 operating near 1720 nm. One advantage of such aconfiguration can be that all of the fiber parts can be spliced togetherto result in an all-fiber, monolithically integrated, no moving partslight source. In this particular example, the pump fiber laser 804 canbe a cladding pumped fiber amplifier 801 with a feedback loop 802 aroundthe amplifier to cause lasing. In one non-limiting example, an isolator803 can be placed in the ring cavity of the pump laser to cause thelasing to be unidirectional. In this case, the cladding pumped fiberamplifier 801 can be an erbium/ytterbium doped amplifier operating near1550 nm. The pump laser light can then be coupled to a cascaded Ramanoscillator 805, where the fiber 806 can be a single-mode fiber and twosets of Bragg gratings 807 can be used to wavelength shift out to near1720 nm.

In one embodiment, a specific example of the mid-infrared fiber laseroperating at approximately 1708 nm is shown in detail in FIG. 9. The toppart of the figure illustrates one embodiment of the pump fiber laser900 details, while the bottom part of the figure illustrates oneembodiment of the cascaded Raman oscillator 950 details. In the pumpfiber laser, the gain fiber 901 can exemplary be an erbium-ytterbiumdoped, double clad fiber. In one embodiment, the length of the gainfiber can be between 3 and 6 meters. One or more pump laser diodes 902can be used to excite the gain fiber 901. In one embodiment, the pumplasers 902 can operate at wavelengths between approximately 935 nm and980 nm, and between 2 and 18 pump laser diodes may be used. The one ormore pump laser diodes 902 can be combined using a power combiner 903,and then the combined pump laser diode power can be coupled to the gainfiber 901. In this particular example, the pump laser diodes 902 can becoupled into the gain fiber 901 in a counter-propagating direction tothe signal in the oscillator. However, the pump laser diodes could alsoco-propagate with the direction of the signal in the oscillator. Afterthe pump combiner 903, a part of the output of the gain fiber can beseparated at a power tap 904 and then feed back to the input using afeedback loop fiber 907. In the loop, an isolator 905 can also beinserted to permit unidirectional operation and lasing (in thisparticular example, the pump fiber laser 900 resonates in acounter-clockwise direction). Other elements may also be inserted intothe ring cavity, such as additional taps 906. Although one particularexample of a pump fiber laser 900 is described, any number of changes inelements or their positions can be made consistent with this disclosure.For example, the pump laser can be a high powered semiconductor laser, asolid state laser, a nonlinear crystal laser, or any combination ofthese.

The bottom of FIG. 9 illustrates one embodiment of a cascaded Ramanoscillator 950 for shifting the pump fiber laser output wavelength to alonger signal wavelength 951. The center of the oscillator is a Ramangain fiber 952, which in this particular embodiment can be a standardsingle mode fiber SMF. The length of the SMF can be in the range of 300m to 10 km, and as an example in this embodiment may be closer toapproximately 5 km. Any number of fiber types, including highnonlinearity fibers, mid-infrared fibers, high numerical aperturefibers, or photonic crystal fibers, can be used consistent with thisdisclosure. The Raman gain fiber 952 can be surrounded by a plurality offiber Bragg gratings FBG, 953, 954 and 955. In this particularembodiment, two cascaded Raman orders are used to transfer the pumpoutput wavelength 908 near 1550 nm to the longer signal wavelength near1708 nm. Hence, in FIG. 9 there can be two sets of fiber Bragg gratings.

As an example, the inner grating set 953 can be designed to provide highreflectivity near 1630 nm. The reflectivity can be in the range of 70 to90 percent, and in this particular embodiment can be closer to 98%. Theouter grating set 954 and 955 can be designed to reflect light near 1708nm (i.e., the desired longer signal wavelength). The first fiber Bragggrating 954 can have high reflectivity, for example in the range of 70to 90 percent, more preferably closer to 98%. The second fiber Bragggrating 955 also serves as the output coupler, and hence should have alower reflectivity value. As an example, the reflectivity of grating 955can be in the range of 8 to 50 percent, more preferably closer to 12%.

Moreover, to remove the residual shifted pump light from the first orintermediate orders of Raman shifting, WDM couplers can be usedsurrounding the oscillator, such as 956 and 957. In this particularembodiment, the WDM couplers 956 and 957 are 1550/1630 couplers (i.e.,couplers that pass light near 1550 nm but that couple across or outwavelengths near 1630 nm). Such couplers can help to avoid feedback intothe pump fiber laser 900 as well as minimize the residual intermediateorders in the longer signal wavelength 951. It may also be beneficial toadd an isolator between the pump fiber laser 900 and the cascaded Ramanoscillator 950 to minimize the effects of feedback. Although onespecific example is provided for the cascaded Raman oscillator 950, anynumber of changes in the components or values or additional componentscan be made and are intended to be covered in this disclosure.

FIG. 10A illustrates a block diagram of yet another embodiment of amid-infrared fiber laser 1000 that operates near 1212 nm. Whereas FIGS.8 and 9 use a ring cavity pump fiber laser, FIG. 10 uses a linear cavitypump fiber laser. Either of these configurations or other versions ofthe pump fiber laser can be used consistent with this disclosure. Inthis particular example, the pump fiber laser 1004 can be a claddingpumped fiber amplifier 1001 surrounded by fiber Bragg gratings 1002 and1003 around the amplifier to cause lasing. In this case, the claddingpumped fiber amplifier 1001 can be a ytterbium doped amplifier operatingapproximately in the wavelength range between 1050 and 1120 nm. The pumplaser light can then be coupled to a cascaded Raman oscillator 1005,where the fiber 1006 can be a single-mode fiber and two sets of Bragggratings 1007 are used to wavelength shift out to near 1212 nm.

In yet another embodiment, a specific example of the mid-infrared fiberlaser operating at approximately 1212 nm is shown in detail in FIG. 10B.The top part of the figure illustrates one embodiment of the pump fiberlaser 1050 details, while the bottom part of the figure illustrates oneembodiment of the cascaded Raman oscillator 1075 details. In the pumpfiber laser, the gain fiber 1051 can exemplary be a ytterbium doped,double clad fiber. In one embodiment, the length of the gain fiber canbe between 3 and 10 meters. One or more pump laser diodes 1052 can beused to excite the gain fiber 1051. In one embodiment, the pump lasers1052 can operate at wavelengths between approximately 850 nm and 980 nm,and between 2 and 18 pump laser diodes may be used. The one or more pumplaser diodes 1052 can be combined using a power combiner 1053, and thenthe combined pump laser diode power can be coupled to the gain fiber1051. After the pump combiner 1053, it may be beneficial to use one ormore isolators 1055 to avoid feedback into the pump laser diodes 1052.

The pump fiber laser can be formed by using a set of gratings 1054 and1056 around the gain fiber 1051. In one embodiment, the fiber Bragggratings 1054 and 1056 can have reflecting at a wavelength near 1105 nm.The reflectivity of 1054 can be in the range of 70 to 90 percent, and inthis particular embodiment can be closer to 98%. The second fiber Bragggrating 1056 can also serve as the output coupler, and hence may have alower reflectivity value. As an example, the reflectivity of grating1056 can be in the range of 5 to 50 percent, more preferably closer to10%. Other elements may also be inserted into the linear resonatorcavity, such as additional taps. Although one particular example of apump fiber laser 1050 is described, any number of changes in elements ortheir positions can be made consistent with this disclosure.

The bottom of FIG. 10B illustrates one embodiment of a cascaded Ramanoscillator 1075 for shifting the pump fiber laser output wavelength to alonger signal wavelength 1076. The center of the oscillator is a Ramangain fiber 1077, which in this particular embodiment can be a HI-1060fiber, which operates at a single spatial mode at the wavelengths of theytterbium amplifier. The length of the Raman gain fiber 1077 can be inthe range of 300 m to 10 km, and as an example in this embodiment may becloser to approximately 1 km. Any number of fiber types, including highnonlinearity fibers, mid-infrared fibers, high numerical aperturefibers, or photonic crystal fibers, can be used consistent with thisdisclosure. The Raman gain fiber 1077 can be surrounded by a pluralityof fiber Bragg gratings FBG, 1078, 1079 and 1080. In this particularembodiment, two cascaded Raman orders are used to transfer the pumpoutput wavelength 1057 near 1105 nm to the longer signal wavelength near1212 nm. Hence, in FIG. 10B there can be two sets of fiber Bragggratings.

As an example, the inner grating set 1078 can be designed to providehigh reflectivity near 1156 nm. The reflectivity can be in the range of70 to 90 percent, and in this particular embodiment can be closer to99%. The outer grating set 1079 and 1080 can be designed to reflectlight near 1212 nm (i.e., the desired longer signal wavelength). Thefirst fiber Bragg grating 1079 can have high reflectivity, for examplein the range of 70 to 90 percent, more preferably closer to 99%. Thesecond fiber Bragg grating 1080 can also serve as the output coupler,and hence may have a lower reflectivity value. As an example, thereflectivity of grating 1080 can be in the range of 8 to 50 percent,more preferably closer to 25%.

Moreover, to remove the residual shifted pump light from the first orintermediate orders of Raman shifting, WDM couplers can be usedsurrounding the oscillator, such as 1081 and 1082. In this particularembodiment, the WDM couplers 1081 and 1082 are 1100/1160 couplers (i.e.,couplers that pass light near 1100 nm but that couple across or outwavelengths near 1160 nm). Such couplers can help to avoid feedback intothe pump fiber laser 1050 as well as minimize the residual intermediateorders in the longer signal wavelength 1076. It may also be beneficialto add an isolator between the pump fiber laser 1050 and the cascadedRaman oscillator 1075 to minimize the effects of feedback. Although onespecific example is provided for the cascaded Raman oscillator 1075, anynumber of changes in the components or values or additional componentscan be made and are intended to be covered in this disclosure.

Super-Continuum Light Sources or Lasers

The cascaded Raman oscillators, such as in FIGS. 8-10, can beparticularly useful when significant power is desired in a relativelynarrow bandwidth, such as for use in a therapeutic procedure. On theother hand, it can be valuable to have a broadband source or a tunablesource to observe either through absorption or reflection the spectralfeatures associated with a particular type of tissue, such as might bedone in a diagnostic procedure. A super-continuum (SC) light source orlaser can be used for generating broadband light. In an SC laser, a MOPA(master oscillator optical amplifier) type configuration can be used forpumping, which can comprise a seed laser followed by optical amplifiersto boost the power. Then, the broadband light can be generated in anoptical fiber using the nonlinear mechanisms in the fiber. Forwavelengths shorter than about 2.6 microns, fused silica fibers can beused for SC generation, such as standard single-mode fiber,high-nonlinearity fiber, high-NA fiber, dispersion shifted or dispersioncompensating fiber. For wavelengths extending beyond 2.6 microns, the SCgeneration can be achieved in a mid-infrared fiber, such as fluorides,chalcogenides, ZBLAN, tellurite or germanium oxides.

FIG. 11A illustrates a block diagram of one embodiment of a mid-infraredSC fiber laser 1100. In this example, the pump laser comprises a seedlaser diode 1101 followed by several stages of amplification in fiberamplifiers 1102 and 1105. Then, the SC can be generated in thisembodiment in a standard single-mode fiber 1106 followed by amid-infrared ZBLAN fiber 1108. The output 1109 from this source canrange in power up to about 10 W or 40 W time averaged power, and thespectral width at the output can range between approximately 800 nm and4500 nm. As another example, if the super-continuum fiber 1108 isinstead a fused silica fiber, then the range of the super-continuum canrange from approximately 1600 to 1800 nm in one embodiment. The seedlaser diode 1101 can be a telecom-grade, distributed feedback laserdiode operating in the telecom band, which can span for instance 1500 to1600 nm. The pre-amplifier 1102 can be made in a single-modeerbium-doped fiber amplifier. The power amplifier 1105 can generaterelatively high powers by using a doped cladding-pumped or double cladamplifier fiber, doped for example with erbium/ytterbium. Although twostages of amplification are shown in FIG. 11A, any number of stages canbe used, including adding one or more stages of intermediate amplifiers.Also, it can be advantageous to place band-pass filters 1103 andisolators 1104 between amplifier stages to control the background noiselevel and to avoid feedback into the amplifiers.

A particular example of a mid-infrared SC laser 1150 that can generaterelatively high powers is illustrated in FIG. 11B. In one embodiment, a10 mW distributed feedback (DFB) laser diode 1151 emitting at 1542 nmcan be driven by electronic circuits 1152 to provide 400 ps to 2 nspulses at variable repetition rates. The electronic circuits 1152 canalso drive the laser diode to output a pre-programmed pulse patterninstead of fixed repetitive pulses. Also, in this example the opticalpulses can be amplified by three stages of fiber amplifiers—anerbium-doped fiber amplifier (EDFA) pre-amplifier 1154 followed byerbium/ytterbium doped fiber amplifier (EYFA) mid-stage 1155 and poweramplifiers 1156. In one embodiment, the pre-amplifier can use a lengthof single mode erbium doped gain fiber 1157, where the length may bebetween 0.5 m and 5 m, preferably close to 1 m in length. In thisembodiment, the mid-stage amplifier 1155 can employ a length of largercore cladding-pumped gain fiber 1158, where the length can be between0.5 and 5 m, preferably close to 1.5 m in length. The EDFA 1157 can beco-propagation or forward pumped using a pump laser diode 1162,preferably operating around 980 nm. The cladding pumped EYFA 1158 canalso be counter-propagation or backward pumped with a laser diode 1163,preferably operating between 935 nm and 980 nm.

In a multi-stage amplifier such as 1155, the noise performance, i.e.amplified spontaneous emission (ASE), can be determined by the upstreamstages before the power amplifier. To lower the ASE, it can beadvantageous to separate the amplifier into a pre-amplifier 1157 and amid-stage amplifier 1158. Therefore, the ASE after the first stage canbe filtered by a bandpass filter 1159, such as a 100 GHz filter, and thesignal gain in each amplifier stage can be reduced. Optical isolators1160 and 1161 are also advantageously placed between the stages toprotect the system from back-reflection damage as well as reduce thenoise figure and improve the efficiency of the combined amplifiersystem. In one preferred embodiment, a ˜20 dB gain can be obtained inboth the pre- and mid-amplifier for the optical signal while theASE-to-signal ratio can be measured to be less than 1%. The nonlinearbroadening of the optical pulses before the power amplifier can also benegligible. In addition, an optical tap may be used to sample the outputpower of the pre-amplifier and to enable the signal feedback control1153.

In one particular embodiment, the power from the mid-amplifier 1155 isboosted in an all-fiber-spliced, cladding-pumped, EYFA 1156 or 1164before coupling into the SC fiber 1167 and 1169. A cladding-pumped fiberamplifier 1164 can be advantageously used to increase the gain volumeand enable the coupling of multiple pump diodes 1166. In addition, tominimize the nonlinear effects in the amplifier, a short length of gainfiber with a large core diameter and a high doping concentration can beused.

In one embodiment of a 10 W SC generation experiment, the gain fiber1164 is designed with a core diameter of between 8 to 25 microns,preferably around 15 μm, and an effective NA in the range of 0.1 to 0.2,preferably closer to 0.15; thus, the mode field size can be close tothat of the SMF fiber. The EYFA 1164 can be several meters in length, asan example ˜5 m in length. In one embodiment, ten 8 W 976 nm and two 8 W940 nm uncooled multimode pump diodes 1166 can be coupled into the gainfiber through an 18×1 pump combiner 1165. Single spatial mode operationcan be maintained in the EYFA by carefully splicing the gain fiber tothe signal-input SMF fiber and the pump combiner. In this example, theoutput spectrum after the SMF fiber can be broadened and red-shifted to˜2.2 μm primarily due to the break-up of the nanosecond pulses throughmodulation instability (MI) followed by soliton self-frequency shifting.In another embodiment, a 12/130 μm core/cladding diametererbium/ytterbium co-doped fiber with a 0.20 NA can be used as the gainfiber 1164 in the final stage power amplifier 1156.

As a particular example, the SC output 1170 can be generated in atwo-stage process. In the first stage SMF fiber 1167, modulationinstability (MI) can be utilized to break up the nanosecond pulses intofemtosecond pulse trains to enhance the nonlinear optical effects andred-shift the optical spectrum to beyond 2 μm. The SC spectrum can thenbe broadened in the following ZBLAN fiber 1169 through the interplay ofself-phase modulation, Raman scattering and parametric four-wave mixing.

In one embodiment, the SC can be generated by butt coupling 1168 thelight from the 2 m length of SMF fiber 1167 after the EYFA into a pieceof ZBLAN fluoride fiber 1169. Two ZBLAN fluoride fibers have been usedexemplary in the experiments. In the 10.5 W high power SC experiment,the ZBLAN fiber 1169 can be 7 m long and can have a core diameter of 8.9μm, a cladding diameter of 125 μm and an NA of 0.21. In another example,the ZBLAN fiber 1169 can have a length of ˜15 m with a core diameter of10.6 μm, a cladding diameter of 125 μm and an NA of 0.2. Advantageously,all ends of SMF 1167 and ZBLAN 1169 fibers can be angle-cleaved to avoidlight back reflected into the pump system. Although one particularexample of mid-infrared SC generation has been shown in FIG. 11, anynumber of elements can be added or positions changed or parameter valueschanged consistent with this disclosure.

The configuration of FIG. 11 can lead to broadband light coveringseveral octaves, exemplary from about 800 nm to approximately 4500 nm.However, narrower bandwidth SC may in some cases be desired atwavelengths shorter than about 2.5 microns. Several examples of SCsources are illustrated in FIG. 12A. The top SC source of FIG. 12A canlead to bandwidths ranging from about 1400 nm to 1800 nm or broader,while the lower SC source of FIG. 12A can lead to bandwidths rangingfrom about 1900 nm to 2500 nm or broader. Since these wavelength rangesare shorter than about 2500 nm, the SC fiber can be based on fusedsilica fiber. Exemplary SC fibers include standard single-mode fiberSMF, high-nonlinearity fiber, high-NA fiber, dispersion shifted fiber,dispersion compensating fiber, and photonic crystal fibers.Non-fused-silica fibers can also be used for SC generation, includingchalcogenides, fluorides, ZBLAN, tellurites, and germanium oxide fibers.

In one embodiment, the top of FIG. 12A illustrates a block diagram foran SC source 1200 capable of generating light exemplary betweenapproximately 1400 and 1800 nm or broader. As an example, a pump fiberlaser similar to FIG. 11 can be used as the input to a SC fiber 1209.The seed laser diode 1201 can comprise a DFB laser that generates,exemplary, several milli-watts of power around 1553 nm. The fiberpre-amplifier 1202 can comprise an erbium-doped fiber amplifier. In thisexample a mid-stage amplifier 1203 can be used, which can comprise anerbium/ytterbium doped double-clad fiber. A bandpass filter 1205 andisolator 1206 may be used between the pre-amplifier 1202 and mid-stageamplifier 1203. The power amplifier stage 1204 can comprise a largercore size erbium/ytterbium doped double-clad fiber, and another bandpassfilter 1207 and isolator 1208 can be used before the power amplifier1204. The output of the power amplifier can be coupled to the SC fiber1209 to generate the SC output 1210. This is just one exemplaryconfiguration for an SC source, and other configurations or elements canbe used consistent with this disclosure.

In yet another embodiment, the bottom of FIG. 12A illustrates a blockdiagram for an SC source 1250 capable of generating light exemplarybetween approximately 1900 and 2500 nm or broader. As an example, theseed laser diode 1251 can comprise a DFB or DBR laser that generates,exemplary, several milli-watts of power around 1553 nm. The fiberpre-amplifier 1252 can comprise an erbium-doped fiber amplifier. In thisexample a mid-stage amplifier 1253 can be used, which can comprise anerbium/ytterbium doped double-clad fiber. A bandpass filter 1255 andisolator 1256 may be used between the pre-amplifier 1252 and mid-stageamplifier 1253. The power amplifier stage 1254 can comprise a thuliumdoped double-clad fiber, and another isolator 1257 can be used beforethe power amplifier 1254. Note that the output of the mid-stageamplifier 1253 can be approximately near 1553 nm, while thethulium-doped fiber amplifier 1254 can amplify wavelengths longer thanapproximately 1900 nm and out to about 2100 nm. Therefore, for thisconfiguration wavelength shifting may be required between 1253 and 1254.In one embodiment, the wavelength shifting can be accomplished using alength of standard single-mode fiber 1258, which can exemplary have alength between approximately 5 and 50 meters. The output of the poweramplifier 1254 can be coupled to the SC fiber 1259 to generate the SCoutput 1260. This is just one exemplary configuration for an SC source,and other configurations or elements can be used consistent with thisdisclosure. For example, the various amplifier stages can comprisedifferent amplifier types, such as erbium doped fibers, ytterbium dopedfibers, erbium/ytterbium co-doped fibers and thulium doped fibers. Oneadvantage of the SC lasers illustrated in FIGS. 11 and 12 are that theymay use all-fiber components, so that the laser can be all-fiber,monolithically integrated with no moving parts. The all-integratedconfiguration can consequently be robust and reliable.

As yet another example of a mid-infrared light source that can generatelight around 1720 nm to 1800 nm, FIG. 12B illustrates a thulium dopedcladding-pumped fiber laser, along with the absorption and emissionbands for thulium-doped fibers. The top left side of FIG. 12B shows andexemplary absorption spectrum 1270 for thulium doping in a single-modesilica fiber. As an example, one efficient band 1271 to pump the fibercan be around 790 nm, where high-power semiconductor pump lasers areavailable. The top right side 1275 of FIG. 12B illustrates theabsorption cross-section 1276 and emission cross-section 1277 for atypical thulium doped fiber in the wavelength range between 1400 nm and2000 nm. As 1275 shows, the cross-over wavelength where the absorptionand emission intersect 1278 can be approximately 1720 nm, and this canmean that a thulium-doped fiber laser could potentially be made betweenapproximately 1720 nm and 2100 nm.

In a preferred embodiment, a thulium-doped fiber laser 1280 can beimplemented as illustrated in the bottom of FIG. 12B for mid-infraredselective damage. One or more pump laser diodes 1281 can be used, wherethe pump laser diode wavelengths can be near the absorption band 1271around 790 nm. The pump lasers can be combined using a pump combiner1282, and then the combined light can be coupled to the gain fiber 1286.Optionally, one or more isolators or spectral filters 1283 can be usedto minimize feedback into the pump laser diodes 1281. The gain fiber1286 can be a thulium-doped fiber amplifier, and in one preferredembodiment the gain fiber 1286 can be a double-clad fiber or acladding-pumped fiber. The resonator 1280 can be formed by placingreflectors surrounding the gain fiber 1286, where the reflector on theleft (e.g., 1284) can transmit the pump wavelengths but reflect thelasing output wavelength 1287. The reflector on the right (e.g., 1285)can also serve as the output coupler and should be at least partiallytransmitting and partially reflecting at the lasing output wavelength1287. In the particular embodiment to FIG. 12B, a fiber Bragg grating1284 can be used on the left side, and another fiber Bragg grating 1285that also serves as the output coupler can be used on the right side ofthe cavity surrounding the gain fiber 1286. Although one embodiment of athulium-doped fiber laser 1280 is illustrated in FIG. 12B, the variouselements in the configuration can be placed at alternative locations,and other elements may also be added or removed from this configurationconsistent with this disclosure.

In one particular example, it may be advantageous to have thethulium-doped fiber laser 1280 operate at wavelengths near 1720 nm orout to 1750 nm, such as when the absorption in adipose, collagen and/orelastin have a local maximum. Since these wavelengths are close to thecross-over 1278 between absorption and emission in thulium, severaladditional procedures or elements may be considered for the laser 1280so as to push the wavelengths to shorter than approximately 1750 nm. Inone embodiment, a shorter gain fiber may be used, and the pump power canbe maintained fairly high through the gain fiber to nearly fully invertthe gain fiber. For example, a nearly fully inverted gain fiber willhave more emission than absorption. In another embodiment, the fiberBragg grating 1284 and 1285 reflecting wavelengths can be selected atthe shorter wavelengths desired. Moreover, the output coupling ratio forthe output coupler 1285 may be selected to optimize lasing at theshorter wavelengths. In yet another embodiment, a lossy element may beintroduced into the laser cavity 1280, wherein the lossy element has ahigher loss at the longer wavelengths such as 1750-2100 nm and lowerloss at the shorter wavelengths such as 1700-1750 nm. In a furtherembodiment, bends may be introduced on sections of the fiber in thelaser cavity 1280 to introduce bend-induced loss, since it is known thatbend-induced loss usually increases with increasing wavelength. In analternative embodiment, a seed laser signal may be introduced toward theshorter wavelengths around 1720-1750 nm, thereby effectively decreasingthe loss at these wavelengths. Any one of these or combinations of thesetechniques may be used to cause the thulium-doped fiber oscillator 1280to operate in the wavelengths closer to 1720 to 1750 nm.

Based on the scattering through tissue and water absorption shown forexample in FIGS. 4 and 5, one advantage of using wavelengths near 1210nm or 1720 nm can be the deeper penetration depths that can be achieved.To explore this advantage, the fiber laser configuration of FIG. 9 wasexemplary used on in vitro human skin tissue samples. In one embodiment,FIG. 13 illustrates the depth of damage 1301 obtained in the in-vitrohuman skin samples plotted as a function of laser fluence at 1708 nmincident on the skin sample. The curve 1301 shows that the damage depthcan increase with increased fluence at 1708 nm, and that the penetrationdepth can approach approximately 1.4 mm in the skin sample. Thus, someof the advantages of using mid-infrared wavelengths can be demonstratedusing the various laser configurations of FIGS. 8 through 12.

Although cascaded Raman wavelength shifters, fiber lasers, andsuper-continuum lasers have been described as some exemplary lasers forgenerating mid-infrared light between approximately 1 and 10 microns, amyriad of other laser systems exist and are intended to be includedwithin the scope of this disclosure. In one embodiment, differentcombinations of the laser such as described in FIGS. 8 through 12 can beused beneficially. For instance, the output from a cascaded Ramanwavelength shifter operating near 1210 nm can be combined with theoutput from a cascaded Raman wavelength shifter operating near 1720 nm.One benefit of such a combination might be that different penetrationdepths into a biological tissue can be obtained using the differentwavelengths. In another embodiment, it may be advantageous to combineone or more cascaded Raman wavelength shifters with one or moresuper-continuum lasers. For example, one advantage of such aconfiguration may be the ability for the laser system to perform bothdiagnostics and therapeutic procedures. In addition, different types ofoptical amplifiers and fibers can be used in the differentconfigurations such as shown in FIGS. 8-12. Optical amplifier materialsinclude fibers doped with different constituents, such as erbium,ytterbium, and thulium or co-doped materials such as erbium/ytterbium.Also, different kinds of fibers can be used in any of theseconfigurations, and exemplary fibers can be made at least in part fromfused silica, chalcogenides, fluorides, telluride, ZBLAN, photoniccrystal fibers, etc.

Alternative laser systems can also be used for mid-infrared lightgeneration. For example, other types of fiber lasers can be used,including modelocked lasers, MOPA or master oscillator followed byamplifiers, and fiber oscillators. In one embodiment, solid state laserscan be used that comprise materials including thulium, holmium, erbium,prysadinium, ytterbium, and chromium. In another embodiment, differenttypes of semiconductor lasers can be used, including optically pumpedsemiconductor lasers, lead-salt diode lasers, antimonide diode lasers,lasers based on III-IV and II-VI semiconductor materials, as well asintra-band lasers, such as quantum cascade lasers. In yet anotherembodiment, gas lasers may be used, including carbon dioxide and carbonmonoxide lasers. In a further embodiment, mid-infrared light sources canbe based on nonlinear frequency conversion, such as optical parametricoscillators and amplifiers, difference frequency generation andparametric frequency conversion. As an example, such nonlinear frequencyconversion techniques can use quasi-phase matched materials, includingperiodically-poled lithium niobate PPLN, gallium arsenide GaAs, lithiumtantalite, and ferroelectric crystals of the potassium titanyl phosphatefamily. These mid-infrared lasers as well as any combinations of thesecan be used in the exemplary medical procedures described below.

Laser Beam Output Parameters

The laser beam output that may be used in the healthcare, medical orbio-technology applications can have a number of parameters, includingwavelength, energy or fluence, spatial spot size, and pulse temporalshape and repetition rate. Some exemplary ranges for these parametersand some of the criteria for selecting the ranges are discussed below.These are only meant to be exemplary ranges and considerations, and theparticular combination used may depend on the details and goals of thedesired procedure.

Whereas it may be advantageous in a diagnostic procedure to use abroadband laser such as a super-continuum source, for varioustherapeutic procedures the wavelength for the laser may be selected onthe basis of a number of considerations. In one embodiment, forselective damage it may be advantageous to reduce or minimize theabsorption due to water and blood as well as scattering through tissue.As an example, from FIG. 5 advantageous windows can be from 1200 to 1350nm or 1600 to 1800 nm.

In another embodiment, it may be advantageous to tune the wavelength tonear an absorption peak in a particular type of tissue. For example,FIGS. 6 and 7 illustrate that wavelengths near 1210 nm or 1720 nm cancoincide with local absorption maxima for adipose, collagen and elastin.Also, from FIGS. 6 and 7 it can be seen that the wavelength window near1720 nm falls near a local minimum in water absorption and scatteringloss. In one embodiment, having lower water absorption and scatteringloss, such as near 1720 nm, can advantageously permit deeper penetrationof the laser light into the tissue. For example, near 1720 nm thepenetration depth into skin or typical tissue may be in the rangebetween 0.5 mm to several millimeters, up to perhaps 3 to 4 millimeters.As one example, FIG. 13 illustrates that light near 1708 nm canpenetrate approximately 1.4 mm in skin tissue.

In yet another embodiment, it may be advantageous to have the laserwavelength fall in the so-called eye-safe wavelength range. Forinstance, wavelengths longer than approximately 1400 nm can fall withinthe eye safe window. So, from an eye safety consideration there may bean advantage of using the wavelength window near 1720 nm rather than thewindow near 1210 nm. Thus, some of the considerations in selecting thelaser wavelength range from selective tissue absorption, waterabsorption and scattering loss, penetration depth into tissue and eyesafe operation. From a combination of these criteria, the wavelengthnear 1720 nm may be particularly advantageous for selectively damagingadipose, collagen and elastin. However, other criteria or considerationsmay also be used in selecting the particular wavelength, and in thisdisclosure the wavelengths near 1720 nm are merely selected as anon-limiting example. For instance, a combination of 1210 nm and 1720 nmmay be used to obtain different penetration depths or to control thepower density profile into the dermis or other tissue.

Another parameter for the laser can be the energy, fluence, or pulsepower density. The fluence is the energy per unit area, so it can havethe units of Joules/cm². As an example, in dermatological applicationsit can be advantageous to use fluences less than approximately 250 J/cm²to avoid burning or charring the epidermis layer. As illustrated in FIG.13, diagnostic procedures may benefit from having fluences less thanabout 50 J/cm², while therapeutic procedures may benefit from havingfluences in the range of approximately 30 to 250 J/cm², preferably inthe range of 50 to 200 J/cm². In another embodiment, it may even beadvantageous to use lower fluence levels for therapeutic procedures toimpart less pain to patients, for example in the range of approximately30 J/cm² or less. These types of fluence levels may typically correspondto time averaged powers from the laser exceeding approximately 10 W,preferably in the power range of 10 to 30 W, perhaps as high as 50 W ormore. Although particular fluence and power ranges are provided by wayof example, other powers and fluences can be used consistent with thisdisclosure.

Although the output from a fiber laser may be from a single ormulti-mode fiber, different spatial spot sizes or spatial profiles maybe beneficial for different applications. For example, for applicationswhere adipose tissue may be damaged around an organ, it may beadvantageous to either collimate or focus the laser light onto theadipose. In one embodiment, it may also be beneficial to have a linescan rather than individual laser spots exposing the adipose tissue. Onthe other hand, for applications such as dermatology or where light maybe exposed onto an external part of the body, it may be desirable tohave a collimated or expanded beam size. To expand and/or collimate thebeam, one or more lenses or curved mirrors may be used after thedelivery fiber. In one example, the beam waist or spot size can be 3 mmor more, preferably 1 cm or even larger. The larger spot sizes canpermit faster procedure times. For example, a spot size with a diameterin the range of 3 mm to 1 cm can lead to scanning over a patients facewithin 15 minutes by a dermatologist. In yet another embodiment,although the output from a fiber is typically a Gaussian-shaped profile,it may be advantageous to have a spatial beam shape that is moresquare-like. As an example, the square-like spatial mode can be achievedby using an aperture at the output of the fiber and blocking the wingsof the Gaussian-like beam. One reason that the square-like beam shapemay be desirable is that it can have a more uniform light intensityacross the beam. Another advantage of the square-like beam may be thatthe area of the body that is to be treated can be set up or marked as agrid, and then the laser beam can be moved from one grid location toanother. Although particular spatial mode shapes and sizes have beendescribed, any number of other shapes and sizes may be used consistentwith this disclosure.

Various types of damage mechanisms are possible in biological tissue. Inone embodiment, the damage may be due to multi-photon absorption, inwhich case the damage can be proportional to the intensity or peak powerof the laser. For this embodiment, lasers that produce short pulses withhigh intensity may be desirable, such as the output from modelockedlasers. Alternative laser approaches also exist, such as Q-switchedlasers, cavity dumped lasers, and active or passive modelocking.

In another embodiment, the damage may be related to the opticalabsorption in the material, such as the optical absorption curvesillustrated in FIGS. 1 through 7. For this embodiment, the damage can beproportional to the fluence or energy of the pulses, perhaps also thetime-averaged power from the laser. The laser power may be absorbed inthe particular tissue types, such as adipose, collagen and elastin, andthe absorbed energy may then lead to heating within the tissue. For thisexample, continuous wave, pulsed, or externally modulated lasers may beused, such as those exemplified in FIGS. 8 through 12. In oneembodiment, laser pulses that are longer than approximately 100nanoseconds to as long as 10 seconds or longer may be employed.

Particularly in the example when the damage may be related to theoptical absorption, it may be beneficial to also consider the thermaldiffusion into the surrounding tissue. As an example, the thermaldiffusion time into tissue may be in the millisecond to second timerange. Therefore, for pulses shorter than about several milliseconds,the heat may be generated locally and the temperature rise can becalculated based on the energy deposited. On the other hand, when longerpulses that may be several seconds long are used, there can be adequatetime for thermal diffusion into the surrounding tissue. In this example,the diffusion into the surrounding tissue should be considered toproperly calculate the temperature rise in the tissue. For these longerpulses, the particular spot exposed to laser energy will reach closer tothermal equilibrium with its surroundings. In one embodimentcorresponding to the data in FIG. 13, pulse widths of approximately 3sec to 10 sec have been used. The local temperature achieved can also beaffected by cooling. As described in the next section, when a coldwindow or cryo-spray is used, the cooling can remove heat from the topsurface of the exposed tissue. Even with surface cooling, the laserpower level may be adjusted so the heating depth reaches the area ofinterest while the cooling protects the regions above this area.Moreover, another adjustable parameter for the laser pulses may be therise and fall times of the pulses. However, these may be less importantwhen longer pulses are used and the damage is related to the energy orfluence of the pulses.

Beyond having a pulse width, the laser output can also have a preferredrepetition rate. For pulse repetition rates above around 10 MHz, wheremultiple pulses fall within a thermal diffusion time, the tissueresponse may be more related to the energy deposited or the fluence ofthe laser beam. The separation between pulses or a sub-group of pulsesmay also be selected so that the tissue sample can reach thermalequilibrium between pulses. Also, the pulse pattern may or may not beperiodic. In one embodiment, there may be several pulses used per spot,where the pulse pattern is selected to obtain a desired thermal profile.The laser beam may then be moved to a new spot and then another pulsetrain delivered to that spot. In one embodiment, there can be severalseconds of pre-cooling, the laser can be exposed on the tissue forseveral seconds, and then there may also be post-cooling. Althoughparticular examples of laser duration and repetition rate are described,other values may also be used consistent with this disclosure.

Laser Beam Delivery, Cooling and Fractionated Beam

A laser beam delivery assembly can advantageously be coupled to themid-infrared laser, such as those shown in FIGS. 8-12. The design of thelaser beam delivery system can be tailored to the ergonomic andcomfortable usage by a medical practitioner. For example, there can behandles for easy gripping, switches or triggers that can be controlledby foot or fingers, and a flexible cord connecting the delivery head tothe laser system. In one embodiment, the flexible cord can comprise asingle-mode or multi-mode fiber, which may be used to couple the laseroutput to the delivery head or output port of the delivery assembly. Thefiber in the flexible cord may be coupled using a connector to the laseroutput, and this can have the advantage that any damage in the deliveryfiber may not require replacing the fiber in the laser system. Also, byusing such a flexible cord and fiber assembly, the laser system can belocated remotely from the delivery arm, such as under a table or on thefloor, perhaps even in a different room than where the procedure isperformed. In one preferred embodiment, a visible wavelength beam, suchas from a helium neon laser, a light emitting diode or a semiconductorlaser diode, may also be coupled to the delivery fiber. Since themid-infrared wavelengths are not easily viewed by the medicalpractitioner, the visible beam can serve as a tracer beam, permittingthe medical practitioner to observe where the laser beam may be incidenton the tissue sample.

The laser beam delivery assembly may be non-invasive (e.g., appliedexternally to the body, such as in dermatology or ophthalmology) orminimally invasive (e.g., percutaneous or inserted into the body, suchas to reach an organ or cardiology applications). In one embodiment, anon-invasive delivery arm may have light guided through a fiber in theflexible arm, and then the delivery head may have mirrors or lenses atthe end to collimate or focus the light beam from the fiber onto thesample of interest. In a particular embodiment relating to dermatology,it may be desirable to have a spot size onto the tissue ranging indiameter from approximately 3 mm to 1 cm or more. In another embodimentrelating to ophthalmology, it may be desirable to have a focusingarrangement at the delivery head. For example, the delivery head mayhave a tip that can be placed on the surface of the eyeball, and thefocusing arrangement may be adjusted to focus the light from themid-infrared laser into the cornea in a controlled manner such that thefocus of the radiation can be at a predetermined depth. As onenon-limiting example, the focusing elements may focus the laser to adepth of less than about 450 microns in the corneal tissue. In anotherpreferred embodiment, the focusing element may create a beam waist at adepth of about 300 to 400 microns below the anterior of the cornealsurface.

In one embodiment where the laser beam delivery assembly is used forapplying light to the skin, eyeballs or externally to other organs, itmay be advantageous to also have a cooling mechanism at the deliveryhead. For example, the cooling can protect the top layer of the skin,eyeball or organ and can remove heat from the top layers as lightpenetrates into the sample. In the dermatology example, the cooling canbe used to protect the epidermis and the top layer of the dermis. Forinstance, the mid-infrared light may be used to cause selective damageat a depth of 1 to 3 mm, while the cooling protects the epidermis andtop layer of the dermis. In one embodiment, the cooling can be achievedby using a cold window at the end of the delivery head. For example, thecold window can be a sapphire window. One advantage of sapphire materialis that it can have a relatively high thermal conductivity and it canalso be transparent in the mid-infrared wavelength range. Cooling can beachieved by flowing chilled water or other cooling fluid from a pumpingsystem to the window at the end of the delivery head. As an example, thetemperature at the head may be controlled by the flow rate or thetemperature of the fluid bath at the pumping system. In yet anotherembodiment, a cryogenic spray system may be used to cool the tissue inthe vicinity of the delivery head, and the timing of the sprays can beadjusted to achieve the desired cooling. In either case, there can bepre-cooling, simultaneous cooling, and/or post-cooling at the time oflaser exposure to the tissue.

There may also be alternative designs for the laser beam deliveryassembly for percutaneous or minimally invasive procedures, such asthose used to reach an organ or artery in the body. The catheter orsystem for snaking into the body should be made relatively thin, and theflexible assembly should be capable of being manipulated by the medicalprofessional external to the body to guide the catheter to theappropriate location. In one embodiment, there may be a radio opaquematerial at or near one end of the catheter, so the catheter can beguided using an x-ray or some other imaging system. The catheter mayalso comprise mirrors or lenses to collimate or focus the light eitherstraight or at some desired angle. In some instances, it may also bedesirable to have the catheter be rotatable over a range of angles. Inanother embodiment, the catheter may also have a camera or imagingsystem, so the medical professional can view on a monitor the image atthe end of the catheter. In yet another embodiment, the catheter mayalso have a suction or removal system for removing debris or damagedtissue from in front of the catheter tip or surroundings. For example,it may be desirable to have a suction system to remove melted or damagedfat from around the catheter. This may be useful so the damaged adiposedoes not become self-limiting, in the sense that the fat in front of thelaser beam can prevent the laser from further penetrating into thetissue. Although particular details of laser beam delivery have beendiscussed, additional elements or combinations can be used consistentwith this disclosure.

For either the non-invasive or minimally invasive laser beam deliverysystem, other modifications may also be made, such as using afractionated laser beam. In one embodiment, a fractional beam maythermally alter approximate microscopic treatment columns in the tissue,while leaving intervening areas of the tissue between the columnssubstantially undamaged. In this example, since only a fraction of thetissue can be modified, untreated areas may be able to repopulate thetreatment columns, thereby reducing recovery time and avoiding adverseevents. In one example, the fractionated laser beam can lead tobeneficial procedures in dermatology. In one particular embodiment ofskin tightening or rejuvenation, in the approximate columns where thelaser beam is exposed, the exposed tissue may be in tension due toshrinkage of collagen by the heat generated by the laser beam. Thistension then may close the voids, tightening the skin and reducing thewrinkles. Thus, in some embodiments the fractional laser beam treatmentcan shorten the wound healing process by allowing the tissue between theareas of the laser exposed to help in the recovery.

The fractionated laser beam may be added to the laser delivery assemblyor delivery head in a number of ways. In one embodiment, a screen-likespatial filter may be placed in the pathway of the beam to be deliveredto the biological tissue. The screen-like spatial filter can have opaqueregions to block the light and holes or transparent regions, throughwhich the laser beam may pass to the tissue sample. The ratio of opaqueto transparent regions may be varied, depending on the application ofthe laser. In another embodiment, a lenslet array can be used at or nearthe output interface where the light emerges. In yet another embodiment,at least a part of the delivery fiber from the mid-infrared laser systemto the delivery head may be a bundle of fibers, which may comprise aplurality of fiber cores surrounded by cladding regions. The fiber corescan then correspond to the exposed regions, and the cladding areas canapproximate the opaque or areas not to be exposed to the laser light. Asan example, a bundle of fibers may be excited by at least a part of thelaser system output, and then the fiber bundle can be fused together andperhaps pulled down to a desired diameter to expose to the tissue samplenear the delivery head. In yet another embodiment, a photonic crystalfiber may be used to create the fractionated laser beam. In onenon-limiting example, the photonic crystal fiber can be coupled to atleast a part of the laser system output at one end, and the other endcan be coupled to the delivery head. In a further example, thefractionated laser beam may be generated by a heavily multi-mode fiber,where the speckle pattern at the output may create the high intensityand low intensity spatial pattern at the output. When referring to“coupling” in this disclosure, it is intended to cover both the cases ofdirectly coupling and indirectly coupling (i.e., there can be additionalintervening elements). Although several exemplary techniques areprovided for creating a fractionated laser beam, other techniques thatcan be compatible with optical fibers are also intended to be includedby this disclosure.

The discussion to this point in the disclosure has been more about thetissue properties, laser designs, laser output parameters, and deliveryof the laser to a patient. In the following, applications of the laserto different medical fields and different tissue types will be describedin more detail.

Collagen Shrinkage with Heating

Collagen connective tissue is ubiquitous in the human body anddemonstrates several unique characteristics, including strength andresilience in various tissue types. It can provide the cohesiveness andtenacity of the musculo-skeletal system, the structural integrity of theviscera, as well as the elasticity of the integument. Collagen fibersare composed of a triple helix of protein chains, with inter-chain bondscreating a crystalline structure for the collagen. When heatedsufficiently, collagen can transform from the crystalline triple helicalstructure to an amorphous, random coil structure through the breakage ofthe hydrogen bonds linking the protein strands of the triple helix. Thiscan create a thickening and shortening of the collagen fibers as thechains fold and assume a more stable configuration. Temperatureelevation can result in contraction of the fiber to about two-thirds oftheir original lineal dimension (i.e., shrinkage by a third of theoriginal dimension) without changing the structural integrity of theconnective tissue. This collagen contraction can be used for a number ofbeneficial applications in vast areas including, but not limited to,ophthalmology and dermatology.

There is not necessarily a specific shrinkage temperature for collagenreaction. It is believed that the amount of collagen contraction couldbe related to a combination of the time and temperature. For example,for relatively long exposures of several seconds, the shrinkagetemperature can be in the range of 60 to 70 degrees Celsius. It isbelieved that normal stabilized collagen fibers are stable up to atemperature of about 58 to 60 degrees Celsius. Also, normal tendoncollagen can have a shrinkage temperature threshold which is about 2 to4 degrees Celsius less than the corresponding threshold for skincollagen. Therefore, one aspect of this disclosure can be to raise thetemperature of the collagen in the temperature range of approximately 60to 70 C to create thermal shrinkage but not to raise the temperature toomuch higher, which could result in thermal damage to the collagen. Sincethe normal body temperature is about 37 C (98.6 F), this means the laserenergy absorbed could raise the temperature between approximately 10 to33 C, more preferably 23 to 33 C, or in one preferred embodiment between23 to 28 C.

Application of Collagen Contraction to Ophthalmology

The cornea of the eye is a unique example of collagen connective tissuewith the cornea stroma, which accounts for about 90% of the totalthickness of the cornea, demonstrating a high transparency ofcross-oriented sheets or lamellae of collagen (mostly type I collagen).To better understand this application, a review is first provided of thehuman eye structure. FIG. 14 (left side) is a horizontal section of aneye 1400 having a roughly spherical structure with a transparent cornea1401 at the forward central portion, the remainder of the sphere of the“eyeball” being white and opaque sclera 1402 (often called the whites ofthe eye) that is attached to and blends in with the cornea periphery.The eye's light-sensitive retina 1403 extends along the rear and part ofthe forward inner surface of the sclera, and it is connected to anoptical nerve 1404 that extends to the brain. The eye 1400 is disposedwithin any eye socket or orbit typically behind an eyelid.

Positioned behind the cornea is a crystalline lens 1405 supported byzonular ligaments 1406, and the lens is capable of shape changes thatenable the eye to focus on objects at various ranges. The eye's iris1407 is positioned between the cornea and lens to divide the spaceforward of the lens into an anterior chamber 1408 and posterior chamber1409 that are filled with aqueous humor. The space behind the lens isfilled with a clear gel-like body 1410 called the vitreous humor.

The right side 1450 of FIG. 14 is an enlargement of the cornealcross-section 1401 to show the various layers of the cornea. Theoutermost or anterior layer is the epithelium 1451 and its basemembrane. The epithelium is typically about 50 microns thick andaccounts for about ten percent of the total corneal thickness. The nextlayer is Bowman's membrane 1452, which is non-regenerative and which isabout 10-13 microns thick in the human eye. The main body of the corneais the stroma 1453, which accounts for about 90 percent of the totalcorneal thickness. The stroma is composed of clear sheets of collagenousmaterial, and most of this is type I collagen. The stroma is backed byDescemet's membrane 1454, which is about 5-10 microns in thickness.Finally, the innermost or posterior layer of the cornea is theendothelium 1455, which is a single layer of non-reproducing flattenedcells of about 4-5 microns thickness.

Although the geometry of the cornea is complex, it has surfaces that areapproximately concentric and spherical, the radius of curvature of theouter or anterior surface typically being about 8 millimeters. Thecorneal diameter is about 11 mm, and the total thickness at the cornealcenter is about 0.55 mm (550 microns). Thus, the thickness of the stromais in the range of 450 to 500 microns.

About three-fourths of the eye's refractive power can be determined bycorneal curvature, and shape modification of this element of the eye'soptical system thus provides a useful tool for correction of refractiveerrors. The change in shape can be provided by heating the collagen-richstroma. However, a problem with heating the eye can arise in thepossibility of damage to the epithelium and Bowman's membrane on theanterior side of the cornea, as well as Descemet's membrane and theendothelium on the corneal posterior. Therefore, it may be desirable tominimize the heating effects in these sensitive membranes while stillobtaining the desired 60 C to 70 C temperature range in the stroma.Thus, it can be advantageous to have a laser wavelength that may beselectively absorbed in the collagen-rich stroma, such as mid-infraredwavelengths in the vicinity of 1720 nm. Other wavelengths can be usedconsistent with this disclosure as well, such as 1210 nm or around 2300nm as non-limiting examples.

In one embodiment, an optional supplement to the mid-infrared laserexposure is to borrow on techniques similar to that used in LaserAssisted in-Situ Keratomileusis (LASIK) surgery. For example, in LASIK acorneal flap is created in some examples using a mechanical blade or afemto-second laser. In exemplary instances, the flap thickness may rangebetween approximately 150 and 200 microns. Thus, the residual stromaleft after the flap is of order of or greater than 250 microns. Then, inmany cases an excimer laser is used to ablate at least a portion of thestroma to achieve the desired reshaping of the cornea.

Borrowing from these LASIK techniques, in one embodiment the cornealflap may be created, thus sparing the epithelium 1451 and vulnerableBowman's membrane 1452 from the laser heating. With the flap lifted orput aside, the remaining corneal stroma 1453 may then be exposed to themid-infrared radiation to achieve the desired collagen shrinkage toreshape the cornea. The selectivity can still be advantageous, so thatthe heating can be localized and damage to the Descemet's membrane 1454and endothelium 1455 may be avoided.

Because of the selectivity in absorbing in the collagen-rich areas, oneadvantage of using mid-infrared wavelengths for light exposure could bethat a flap-less LASIK type procedure could be performed, which would berelatively non-invasive. For example, most of the complications of LASIKsurgery currently are associated with the cutting of the flap andhealing of the flap after surgery. Also, infections of the eye canresult from the cutting of the corneal flap. By exposing the cornealtissue and having absorption of the light energy directly in the corneawithout cutting off the corneal flap, many of the complications of LASIKcould be minimized. Although the amount of refractive index correctionin the cornea may be more limited using the flap-less LASIK procedure,the non-invasive nature of the procedure should be attractive in manyinstances. Also, the flap-less LASIK procedure could benefit from toplayer cooling using a cold window, as further described below.

Beyond using the selectivity of the mid-infrared wavelengths forophthalmology procedures, it could also be beneficial to use surfacecooling or a cold window to cool the surface of the eye before, during,and after exposing the laser light. This could still be a non-invasiveprocedure, since the cold window or surface cooling could be applieddirectly to the surface of the eye. As laser light is incident on theeye, the light energy may be highest near the outer surface, and thenthe light energy will decrease as the light penetrates further into theeye because of absorption and scattering. Hence, it is very likely thatthe outer layers of the eye are more vulnerable to heating damage. Bysurface cooling or placing a cold window next to the eye, the heat canbe removed from the top layers, thereby lowering the possibility ofthermal damage in the unwanted areas. This can enhance the collagenheating in the corneal stroma, while avoiding damage particularly in theepithelium and Bowman's membrane, as an example. Although surfacecooling is described, many other embodiments to cool the top layers orconduct heat away could be used consistent with the disclosure. Forexample, a cryogenic spray could be used, where cold gases or emissionis sprayed onto the surface of the eye.

Although several examples are provided for alternative techniques formid-infrared laser usage in an ophthalmology procedure, there arenumerous other techniques in ophthalmology that can benefit from using amid-infrared laser for collagen shrinkage or localized, selectiveheating or damage. Another benefit of using mid-infrared laser light inophthalmology applications, particularly at wavelengths near 1720 nm,can be that the wavelength lies in the eye safe wavelength range. Forexample, since the aqueous humor and vitreous humor do not transmiteffectively wavelengths beyond approximately 1400 nm, using themid-infrared light near 1720 nm can avoid or minimize risk of damage tothe retina from residual radiation from the corneal reshaping procedure.

Also, other modifications to the laser exposure can be made and areincluded as parts of this disclosure. For example, the collagenshrinkage using mid-infrared light can be preceded by application of areagent to the collagen tissue for reduction of the shrinkage thresholdtemperature. Examples of preferred reagents include hyaluronidase andlysozyme. It has been reported that with application of such reagentsthat the collagen shrinkage temperature can be lowered by 10 C to 12 C.This has advantages because it means less laser energy can be depositedin the stroma. Thus, there can be less chance of damage to thesurrounding tissue. Moreover, the gap between collagen shrinkage energyand collagen damage energy can be enlarged. Although one example isshown of modifying the collagen shrinkage procedure, any number ofimprovements in terms of spatial focusing, additional chemicalapplications, or laser alternations can be made consistent with thisdisclosure and are intended to be covered by this disclosure.

In yet another embodiment, the mid-infrared light treatment may beaccompanied by techniques to prevent or minimize regression of collagenshrinkage. If the collagen of the stroma or other sections of the eyeare damaged sufficiently, then the body may react using, for example,its natural wound healing processes. Consequently, loss of the collagenshrinkage effect as a function of time, otherwise known as regression ofthe desired effect, can result from the wound repair process. Severaltechniques may be used to try to minimize the regression. In oneexample, by controlling the exposure time and power level or fluence ofthe mid-infrared appropriately, collagen shrinkage might be obtainedwithout the damage that leads to the wound repair mechanisms. In thisinstance it may be advantageous that the light can be absorbedselectively in the collagen-rich stroma and that by being near the peakof the local absorption, the heating can be accomplished moreefficiently. In addition, the cooling of the outer layers of the eye mayalso be advantageous, since damage in the outer layers may be avoided,thereby not leading to the body initiating a wound healing process. In afurther embodiment, pre-heating or pre-cooling may lead to a shockresponse in the eye, which then increases the tolerance of the eye tolaser treatment, thereby increasing the threshold for the wound healingprocesses. In yet another embodiment, chemicals may be applied to theeye that may counter-act or inhibit the wound healing mechanisms in theeye. The goals of such procedures may be to increase the time orpermanence of the collagen shrinkage effect.

Treatment Examples in Ophthalmology

Keratoconus can be one example of applying the above concepts to thefield of ophthalmology. Keratoconus is a degenerative disorder of theeye where structural changes within the cornea cause it thin and changeto a more conical shape than its normal gradual curve. It is typicallydiagnosed in the patient's adolescent years and attains its most severestate in the twenties and thirties. Keratoconus is the most commondystrophy of the cornea, affecting around one person in a thousand.Also, between 10% and 25% of cases of Keratoconus will progress to apoint where vision correction is no longer possible, thinning of thecornea becomes excessive, or scarring as a result of contact lens wearcauses problems of its own.

Alternative laser-based procedures are needed because LASIK can beincompatible with Keratoconus and other corneal thinning conditions asremoval of corneal stromal tissue will further damage an already thinand weak cornea. Contact lenses are the primary treatment for mostpatients with Keratoconus. Severe cases may require cornealtransplantation. This is a surgical procedure that replaces theKeratoconus cornea with healthy donor tissue. In this process much ofthe central cornea of the Keratoconus patient is removed and is replacedwith the cornea of a recently deceased person.

Some newer technologies may use high frequency radio energy, where theenergy shrinks the edges of the cornea, which in turn pulls the centralarea back to a more normal shape. The procedure is known as ConductiveKeratoplasty, which uses radiofrequency to strategically heat and shrinktiny parts of the collagen in the cornea. However, the radio frequencyenergy cannot be highly focused, and the radio frequency heating mayheat anything with water content, which may not be selective to thestroma. Also, this is not a non-invasive procedure, since needles orantennas are inserted into the eye to localize the RF energy in certainregions.

An advantageous treatment for Keratoconus that may avoid the need forcorneal transplantation could be to use the collagen shrinkagetechniques described above. For example, the mid-infrared light can befocused using an appropriate lens system, and the beam waist could betailored to lie around the middle of the stroma, in one embodiment inthe range of 300 to 400 microns depth below the anterior cornealsurface. Also, the mid-infrared light could be focused around the edgesof the cornea in the stroma, collagen-rich areas, so that the collagenshrinkage may shrink the edges of the cornea and pull the cornea back toa more normal shape. In an alternate embodiment, the mid-infrared lightcould be focused closer to the center of the corneal stroma, thereby,for example, shrinking the center peak in the cornea. In one example,the stroma could be heated to a temperature in the range of 60 C to 70C, while minimizing heating in the surrounding sensitive membranes,particularly in the endothelium.

The stroma can be selectively heated using a combination of two effects.First, selecting a wavelength corresponding to a collagen peak with lesswater absorption can cause more heating in the collagen-rich stroma.Second, by focusing the mid-infrared laser beam toward the centerthickness of the stroma, the light intensity (power per unit area) canbe higher in the stroma than in the surrounding membranes. In onepreferred embodiment, the laser beam can have a beam waist that isapproximately centered on the stroma central thickness, and the focalspot size can be adjusted so that the confocal parameter or Rayleighrange (i.e., the distance over which the beam diffracts to twice itssmallest beam waist) is adjusted to be approximately less than thethickness of the corneal stroma, which is of order of 450 microns.Earlier reports claim that the collagen shrinkage appears to bepermanent, with the potential of little or no lasting opacity of thetreated site resulting from the mid-infrared light exposure. If thecollagen shrinkage is not permanent, then the non-invasive procedure canbe repeated after some length of time. For example, a Keratoconuspatient may return for mid-infrared laser treatment every six months totouch-up any reshaping of the corneal layer. In yet another embodiment,some of the techniques described earlier for preventing regression canbe used in conjunction with the collagen shrinkage procedure.

Although Keratoconus is described as one non-limiting example, there aremany other ophthalmology procedures where the collagen shrinkage withlaser exposure can be advantageously used. For example, in oneembodiment the collagen shrinkage with heating could be useful forpromoting collagen cross-linking. In the collagen cross-linking, newbonds can form across adjacent collagen strands in the stromal layer ofthe cornea, which recovers and preserves some of the cornea's mechanicalstrength. In one embodiment, the cross-linking could be used to attachcornea transplants or to join segments of cornea that are separated forany reason.

In yet another embodiment, different refractive index changes in thecornea or “refractive power correction” can be corrected by properspatial placement of the laser beam exposed regions. For example, tocorrect for hyperopia (far-sightedness or long-sightedness), it may beadvantageous to have the laser beam focused at locations on the side orperiphery of the cornea. For example, in hyperopia it may be desirableto increase the steepness of the cornea to increase the refractive lenspower. On the other hand, to correct for myopia (near-sightedness orshort-sightedness) it may be advantages to have the laser beam focusedcloser to the center of the cornea. For instance, for myopia treatmentit may be desirable to flatten the center of the cornea to decrease therefractive power of the cornea, and in one embodiment a diameter ofapproximately 6 mm may be used around the center of the cornea. Sincemyopia is among the most common eye ailments, treating myopia usingmid-infrared light in an approximately non-invasive procedure may have alarge impact. However, since the center of the cornea is more likely tobe exposed to mid-infrared radiation in treating myopia, it may beimportant to control the laser exposure time, power level or fluence, sothat damage and opacity can be avoided in the cornea and surroundingareas. As the collagen shrinkage is accomplished using the mid-infraredlight, some of the issues to monitor include the clarity of the corneallayer after laser treatment and any damage to the outer layers, such asthe epithelium or Bowman's membrane. Surface cooling or application of acold window, for example, could also help in avoiding damage to theouter layers.

Although LASIK is a widely used procedure, it is contraindicated in anyof the corneal thinning conditions, or conditions where the cornea isweakened. Consequently, one general area where collagen shrinkage withmid-infrared light exposure can be advantageously used is in proceduresinvolving a thinned or weakened corneal layer. Also, since themid-infrared light exposure can be non-invasive (e.g., it does notnecessarily require the moving back of a corneal flap, such as inLASIK), the collagen shrinkage procedures can be performed on patientsto trim or slightly modify the corneal shape. The non-invasive proceduremay also be accompanied by surface cooling or a cold window to avoiddamage to the eye. Also, some of the techniques for avoiding regressionmay also advantageously be used. One advantage of the collagen shrinkagetechnique may be the reversibility of the change, so long as thecollagen shrinkage is achieved without damage. This may be valuable if,for example, proper refractive power correction is not achieved duringthe procedure.

It will be appreciated that there are many other corneal procedures thatcan benefit from this non-invasive technique. For example, astigmatismmay be corrected by having laser light resonant with the collagenabsorption. As one other non-limiting example, the collagen shrinkagemay be beneficial in treating presbyopia. Presbyopia is often called“old eye” and is experienced in many people starting around the age of40-50 years. With presbyopia, it often becomes harder to focus on smallobjects at close distance. As one ages, the lens 1405 can become lessmalleable or the capsule less elastic; consequently, the lens 1405 maynot assume a greater curvature in spite of the reduced tension of thezonules 1411 upon the lens.

The ciliary muscle or body 1412 is a smooth muscle in the eye thatcontrols the eye's accommodation for viewing objects at varyingdistances. The circular ciliary muscle fibers 1412 affect zonular fibers1411 in the eye (fibers that suspend the lens in position duringaccommodation), thereby enabling changes in lens shape for lightfocusing. For example, when the ciliary muscle 1412 contracts, it pullsitself forward and can move the frontal region toward the axis of theeye. This can release the tension of on the lens by the zonular fibers1411, thus causing the lens to become more spherical and able to adaptto shorter range focus. On the other hand, relaxation of the ciliarymuscle 1412 can cause the zonular fibers 1411 to become taut, flatteningthe lens, and thus increasing the long range focus.

In one particular embodiment, an at least partial treatment forpresbyopia can result by exposing at least parts of the ciliary muscleor body 1412 and/or the zonular fibers 1411 to mid-infrared light. Byutilizing the shrinkage of collagen connective tissue at the site of theciliary muscle 1411 and zonular fibers 1412, the ability to control thecurvature of the lens 1405 or to accommodate an enlarged lens 1405 couldbe improved. For instance, by shortening or shrinking the tendinousportions of the ciliary musculature 1411 to increase its mechanicaladvantage, it may be possible to overcome the physiologic laxity in theaccommodative function brought about by presbyopia. Moreover, thecollagen shrinkage could also assist in more accommodating motion of thelens 1405 by tightening the trabecular meshwork of the aqueousfiltration mechanisms in the region near the ciliary 1411. Note,however, that these regions of the eye lie below the sclera tissue 1402.One potential advantage of using mid-infrared light that may beselectively absorbed in collagen can be that the light can transmitthrough the sclera 1402 to the regions near or surrounding the collagentissue in the ciliary muscle 1411 and zonular fibers 1412. Consequently,the procedure to treat presbyopia could be substantially non-invasive.The mid-infrared light treatment can be combined with any number of thetechniques described in this specification. For example, it may beadvantageous to also use surface cooling over the sclera 1402 to avoidthermal damage in this tissue layer. Also, chemicals, drugs or othertechniques to avoid or minimize regression may be used advantageouslywith the mid-infrared light treatment.

Selective Damage in Dermatology

Another example of the application of mid-infrared lasers for selectivedamage to the human body is in dermatology. Before describing thisapplication in more detail, a review is first provided of the skin,which is the largest organ in the body and comprises about 15 percent ofthe body weight. The skin 1500 is composed on three main layers:epidermis 1501, dermis 1502, and subcutaneous tissue 1503 (FIG. 15). Theepidermis 1501 is the topmost layer of the skin, and it comprises threetypes of cells: keratinocytes, melanocytes and Langerhans cells.Keratinocytes, the cells that make the protein keratin, are thepredominant type of cells in the epidermis. The total thickness of theepidermis is in the range of 0.1 to 1 mm, depending on the location onthe body. At the lowermost portion of the epidermis are immature,rapidly dividing keratinocytes. As they mature, keratinocytes losewater, flatten out, and move upwards. At the end of their life cycle,they reach the uppermost layer of the epidermis call the stratumcorneum. The stratum corneum is made up mostly of dead keratinocytes,hardened proteins (keratin) and lipids, thereby forming a protectivecrust. Dead cells from the stratum corneum continuously fall off and arereplaced by new ones coming from below. In fact, the skin completelyrenews itself every three to five weeks.

Another group of cells in the epidermis 1501 are the melanocytes, whichproduce melanin, the pigment responsible for skin tone and color.Finally, Langerhans cells are part of the immune system of theepidermis, and they prevent unwanted foreign substances from penetratingthe skin.

The dermis 1502 is the middle layer of the skin located between theepidermis and subcutaneous tissue. It is the thickest of the skin layersand comprises a tight, sturdy mesh of collagen 1507 and elastin fibers1508. Both collagen 1507 (mostly Type I) and elastin 1508 play a bigrole in the skin function: collagen is responsible for the structuralsupport and elastin for the resilience of the skin. The fibroblasts inthe dermis synthesize collagen, elastin and other structural molecules.

The dermis also contains capillaries and lymph nodes. The former help tooxygenate and nourish the skin, while the latter help to protect theskin from invading microorganisms. In addition, the dermis containssebaceous glands 1505, sweat glands 1506, hair follicles 1504, as wellas a relatively small number of nerve and muscle cells. Sebaceous glands1505 are lipid-rich glands, which are located around hair follicles1504. The sebaceous glands 1505 produce sebum, which is an oilyprotective substance that lubricates and waterproofs the skin and hair.Overproduction of sebum can lead to skin ailments, such as oily skin oracne.

Subcutaneous tissue 1503 is the innermost layer of the skin locatedunder the dermis 1502 and comprising mostly fat or adipose. Thepredominant type of cells in the subcutaneous tissue 1503 is adipocytesor fat cells. Subcutaneous fat 1503 acts as a shock absorber and heatinsulator, protecting underlying tissues from cold and mechanicaltrauma.

The dermis 1502,1602 is the layer of the skin 1600 responsible for theskin's structural integrity, elasticity, and resilience. Wrinkles 1605arise and develop in the dermis (FIG. 16). Wrinkles 1605 are mainlyformed by the distortion of the dermis 1602 due to loss of elasticityinduced by decrease of collagen and elastin fibers. Therefore, ananti-wrinkle treatment can be effective in one embodiment only if thetreatment can reach as deep as the dermis. For example, light treatmentsthat use a wavelength of light that do not penetrate down to the dermiswill probably not be efficacious in treating wrinkles 1605. Also,typical collagen and elastin topical creams are not generally effectivebecause collagen and elastin molecules are too large to penetrate theepidermis 1601.

Non-Ablative Skin Rejuvenation, Tightening, Wrinkle Removal

Non-ablative, non-invasive skin tightening, skin rejuvenation andwrinkle removal could be advantageously accomplished using mid-infraredlight. The dermis 1501, 1602 is composed mainly of collagen 1507,elastin 1508 and sebum. Both collagen 1507 and elastin 1508 can beresponsible for renewing skin cells and maintaining a youthfulappearance of the skin. Skin tightening has been achieved in earliersystems, for example, using either radio frequency or flash lampsystems. In the radio frequency systems, the RF is absorbed in thesubcutaneous fat layer 1503, and the heat generated from this transfersto the dermis 1502 and is used for stimulating collagen growth. On theother hand, flash lamp systems with light covering approximately 1100 to1800 nm have been used for skin rejuvenation, but these systems try totrigger new collagen growth by using collagen contraction throughheating of the surrounding water in the dermis 1502 and then transfer ofthis heat to the collagen. However, both of these systems can beinefficient and may deliver too much energy to the skin, leading topotential unnecessary harm to the epidermis 1501 or pain to the patientsundergoing the treatment.

In one embodiment, a more efficient use of the laser light can beachieved by using wavelengths in the vicinity of local peaks inabsorption of the constituents of interest in the dermis 1502, 1602. Forexample, as FIG. 7 illustrates, collagen 703 elastin 704 and adipose 702all can have a local peak absorption near 1720 nm 706. This window alsocan correspond to a local minimum in water absorption 701, and thescattering can also be low at the longer wavelengths. Another exemplarywavelength window can be in the neighborhood of 1210 nm 705: however,the peaks may not be as precisely lined up, the absorption of collagen703, elastin 704 and adipose 702 appears to be considerably weaker, thewater 701 can have a local peak in absorption in this window, and thescattering through the tissue can be higher at this shorter wavelength.

In the embodiment using mid-infrared light near 1720 nm 706, the lightcan be preferentially absorbed in the collagen 703, elastin 704, andadipose or sebum/adipose 702, leading to the desired heat generation inthe dermis. The heat generated can then lead to collagen contraction aswell as rejuvenation of the collagen 1507 and elastin 1508 tissue. Theheated collagen can transform from the crystalline triple helicalstructure to an amorphous, random-coil structure through the breakage ofthe hydrogen bonds linking the strands of the triple helix. Hence,non-ablative skin rejuvenation, skin tightening and/or wrinkle removalcan be achieved with potential efficient use of the optical energy.

Another advantageous aspect of using mid-infrared light for skintreatment can be that a deeper penetration into the skin can beachieved. The epidermis 1501 may be of order 0.1 mm thick, while thedermis 1502, 1602 can be about 4 mm in thickness. For treatment of thedermis 1502, 1602, it may be desirable for the heat penetration depth tobe about 1 to 2 mm, perhaps with some heating down as far as 4 or 5 mm.In one particular embodiment, penetration of laser light in the depthrange of approximately 0.5 mm to 1.5 mm may be desirable. In anotherpreferred embodiment, the heating can reach down to the middle or bottomof the dermis layer 1502, 1602. Based on the water absorption 402 andscattering 401 through skin tissue (FIG. 4), the penetration depth intothe skin 1500 can be estimated. For example, as shown in FIG. 5, thetotal absorption and scattering coefficient 501 can be approximately 6.8cm⁻¹ at 1210 nm, which corresponds to an absorption length (inverse ofthe coefficient) of about 1.47 mm. Thus, the light penetration at 1210nm can be of order one to three absorption lengths, or approximately 1.5mm to 4.5 mm in depth. On the other hand, the total absorption andscattering coefficient 501 can be approximately 8.25 cm⁻¹ at 1720 nm,which corresponds to an absorption length of about 1.2 mm. Thus, thelight penetration at 1720 nm can be approximately 1.2 mm to 3.6 mm,which should be comfortably within the mid-range of the dermal layer1502, 1602. As an example, one advantage of heating to a depth of 1 to 2mm can be that the dermal collagen fibers 1507 can be targeted whileallowing a cooling mechanism to protect the epidermis 1501.

The curves in FIG. 7 can lead to preferred embodiments for selectivedamage using mid-infrared lasers in the wavelength window near 1210 nm705 or 1720 nm 706. Of these two window options, in some instances itmay be advantageous to select the longer wavelength window near 1720 nm706. For example, one reason for selecting this longer wavelength windowmay be to operate in the so-called “eye-safe” wavelength range, whichcan correspond to wavelengths longer than approximately 1400 nm. Asecond advantage of the longer wavelength window near 1720 nm 706 fordermatology applications can be that the peaks for the majorconstituents of dermis—namely, collagen, adipose and elastin—allapproximately line up near 1720 nm 706. Therefore, the heat generationcan be synergistic from optical absorption in all these constituents.Finally, for dermatology the efficiency of the optical energy deliverycan be better at 1720 nm 706 than at 1210 nm 705. For example, theefficiency can be higher when the loss or absorption length (inverse ofthe absorption coefficient) is approximately matched for the propagationthrough skin tissue from water absorption and scattering 701 and, forexample, the absorption length in adipose tissue 702. At 1720 nm 706,for instance, the absorption length from water absorption and scatteringcan be 1.2 mm (8.25 cm⁻¹ absorption coefficient), while the absorptionlength for adipose can be approximately 1.12 mm (8.5 cm⁻¹). On the otherhand, at 1210 nm 705, the absorption length from water absorption andscattering can be 1.47 mm (6.8 cm⁻¹), while the absorption length foradipose can be approximately 5 mm (2 cm⁻¹). For light excitation ofadipose, 1720 nm 706 can be more efficient than at 1210 nm 705. At 1210nm the light can be lost more rapidly due to water absorption andscattering 701 in the tissue, and because of the weaker absorption inadipose more light energy will probably be required. To achieve the sameresults, a higher laser power exposure will probably be required at 1210nm 705, which could also mean that the epidermis 1501 and upper dermislayers 1502 are more susceptible to damage or scarring.

Other Advantageous Dermatology Applications

Yet another embodiment of a procedure that could benefit from using amid-infrared selective laser is stretch mark or striae removal. Stretchmarks, also called striae, are a common problem affecting a majority ofwomen who have had children. For example, during pregnancy the skin ofthe abdomen stretches to many times its normal size as the baby grows.After the baby is delivered, the skin's elasticity in the dermiscontracts to bring the abdomen skin back to its normal shape. Duringskin stretching, if the dermis expands too much or too fast, the dermiscan break, split or rupture. These breaks in the dermis of the skincause a wide depressed scar, which is called a stretch mark or striae.

Also, in recent years, the use of steroids has caused stretch marks inmany young men who have worked very hard at body building and fitness.The use of steroid medications also causes striae even without tensionor pulling on the skin. The mechanism of the striae caused by steroidscan be a direct damage or dissolving of collagen in the dermis by thesteroid medication. In addition, rapid growth spurts during adolescenceor even in adults who are weight lifting and have rapid muscleexpansion, can also cause rupture of the dermis and striae.

In one embodiment, repairing stretch marks and striae can requirebuilding new collagen 1507 in the dermis 1502, 1602 of the skin toreplace the lost collagen and tightening of the skin to bring thestretched skin back together. This may be accomplished by heating usinga mid-infrared laser system. For example, when the collagen is heated toa temperature in the range of 60-70 C, the collagen can shrink andtighten, and the collagen can be stimulated to remodel and grow newcollagen. It can also be advantageous to have a treatment where thelaser heating penetrates sufficiently deep into the dermis 1502, 1602,for example in the range of 1 to 2 mm. The dermis layers 1502, 1602 arewhere the collagen regeneration and elasticity of the skin can be mosteffective to recover from the stretch marks or striae.

Another aspect of this disclosure is that the selective absorption incollagen, elastin and adipose can be advantageously used for laser skinresurfacing to treat various kinds of skin flaws, such as sunburns,wrinkles, acne and acne scar removal. Such skin flaws are often treatedusing dermabrasion, which entails removing the topmost layer of the skinvia a sanding procedure. However, this procedure is quite painful, oftenrequiring the use of local anesthesia while applying to a patient. Aftersuch a procedure the skin can be raw and painfully tender, and new skincould take months to grow back. An alternative procedure may be to usechemical peels, which can use chemicals that cause the skin to blisterand finally peel off.

A non-ablative laser procedure could be less painful and moreefficacious for patients with skin flaws. A mid-infrared, non-ablative,laser procedure could work beneath the skin 1500, 1600 surface,stimulating collagen production and tightening the overall tissue.Another advantage of a laser-based technique can be that the laser beamcan be targeted or localized to the region of interest, for example onthe face or body of the patient. Yet another advantage of a selectivelaser damage technique can be that the patient can have a fasterrecovery time and less redness of the treated region, since theselective laser can lead to less damage to vascular fibroblast.

In one non-limiting example, the selective laser procedure can be usedwith patients afflicted with acne and the resulting acne scar tissue.The root cause of acne can be excess sebum production in the lipid-richsebaceous glands 1505, which lie near the side or bottom of a hairfollicle 1504. The sebaceous glands 1505 that cause acne typically liein the region about 0.25 to 1.5 mm below the skin surface. Incidentally,the excess sebum production can also lead to other skin ailments, suchas oily skin. Unfortunately, acne can leave behind unsightly and evendisfiguring scars. Patients afflicted with acne and the resulting scarsmay benefit from a mid-infrared skin treatment that can selectivelytarget and comprise light absorbed in collagen, elastin and adipose. Inone embodiment, mid-infrared light near 1720 nm can be advantageouslyused, since the penetration depth can be well matched to the depths ofthe sebaceous glands 1505. In one non-limiting example, the mid-infraredlight can be selectively absorbed in the sebaceous glands 1505, therebyhalting the excess sebum production. In addition, the selectiveabsorption in the collagen 1507 and elastin 1508 of the dermis can beused to help repair the skin flaws. For example, with the collagenshrinkage and stimulating collagen production, the acne scar tissue canbe replaced with new skin. Therefore, the selective absorption of themid-infrared light in the dermis has the potential to treat the rootcause of acne as well as repair the acne scar tissue.

Although a few dermatology applications have been described, there aremany other applications of the mid-infrared light in dermatology thatare intended to be covered by this disclosure. Therefore, the listedprocedures are provided by way of example, but the disclosure could alsocover many other dermatology applications. For example, yet anotherdermal application that can benefit from mid-infrared light resonantwith the collagen, elastin and adipose is wound healing or dermalremodeling. For example, stimulation of collagen bio-synthesis is oftendesirable in the early stages of wound healing. The heating throughselective absorption in the collagen, elastin and adipose near the woundregion can lead to collagen contraction and skin rejuvenation.

Combining Mid-Infrared Light with Other Dermal Techniques

In describing the dermatology applications, the above description hasjust described using the mid-infrared laser light (exemplary near 1720nm, possibly 1210 nm) directly to the skin to have selective absorptionin the dermis in the collagen, elastin and adipose. However, thisdisclosure is intended to cover combining the mid-infrared lasertreatment with any number of temporal, spatial or procedural techniquesthat are known to be used in dermatology. In one embodiment, it iscontemplated that the laser treatment can be done at different timeperiods. For example, it can be likely that the non-invasive tissuemechanisms relate both to the immediate as well as delayed effects oncollagen. Although initial research studies presumed the collagenshrinkage to be irreversible, newer evidence suggests that the meltingtemperature of collagen can be actually lower than 37 C, and that theremay be a tendency for reversibility. Collagen melting occurs at bodytemperature but the time intervals are relatively long. Consequently,the collagen shrinkage effect may be reversed after several weeks ormonths. Therefore, it may be necessary to repeat the collagen shrinkageevery several weeks or every several months, depending in part on theseverity of the skin changes.

In yet another embodiment of combining different dermatologicalprocedures, it is likely that the mid-infrared light exposure may haveto be combined with protecting the epidermis 1501 and top layer of thedermis 1502 using external cooling, such as a cold window or cryospray.In most non-invasive, non-ablative laser dermatology procedures,external cooling is used to protect the epidermis 1501 and top layer ofthe dermis 1502. There can be pre-cooling, cooling in parallel with thelaser exposure, and post-cooling. Therefore, the cooling of the skin toplayer is contemplated as part of this disclosure of applyingmid-infrared light to the skin to selectively absorb. One benefit ofselective absorption in collagen, elastin and adipose can be that theprocedure may result in less pain to the patient. For example,techniques that rely on absorption in water often require more energyand can also be more painful, since water is throughout the skin. Withthe selective absorption at the mid-infrared wavelengths, lesscollateral heating can occur, which can reduce the pain levelexperienced by the patient. Nonetheless, it still may be desirable touse a local anesthetic to lower the pain felt by a patient when exposingthe laser light.

Another embodiment of using the mid-infrared laser treatment may also beto combine the selective absorption with a fractionated laser beam. Thefractionated laser beam comprises an array of microscopic beams. Withthis array pattern for the beam, the laser can be adapted to make tinywounds in the dermis layer to trigger the nature healing abilities ofthe body. Although several laser procedures may be required, it isbelieved that making the micro-laser damage spots may enhance therecovery of the skin because the undamaged skin surrounding the laserspots will aid in the recovery. It is contemplated that using afractionated laser beam with the mid-infrared light near wavelengthssuch as 1210 nm or 1720 nm can be within the scope of this disclosure.

Yet another embodiment of using mid-infrared laser can be to combine thelaser exposure with topical creams or other substances applied to theskin surface. For example, in some procedures it might be desirable toapply keratin or a related compound to the skin surface, which can alsoaid in the collagen or elastin rejuvenation. In another example,polypeptide growth factors may be applied to the skin, as they arebelieved to play a role in skin healing. In yet another example, localanesthetics may be applied to the skin or a cool pack to relieve painassociated with the light exposure.

In yet another embodiment, the time exposure of the mid-infrared lasermay be varied to obtain different effects. For example, in someinstances the pain felt by the patient can be reduced by using lowerfluence (one example being in the range of less than 30 J/cm²) but forlonger periods of time, for example of order 10 seconds. If the time ofexposure to the laser is very short compared to the time required forheat to diffuse out of the area exposed, namely the thermal relaxationtime, then the temperature rise at any depth in the exposed tissue canprobably be proportional to the energy absorbed at that depth. On theother hand, if the pulse width is comparable or longer to the thermalrelaxation time of the exposed tissue, then the profile of temperaturerise may not be as steep. Conduction of thermal energy can occur at arate proportional to the temperature gradient in the exposed tissue.Consequently, lengthening the exposure time may reduce the maximumtemperature rise in exposed tissue. Different temporal patterns for themid-infrared light are intended to be covered in this disclosure.

Although several embodiments of combining the mid-infrared laserexposure with other dermatology techniques are described, othercombinations are also intended to be covered by this disclosure. Also,combinations of these techniques can also be used consistent with thisdisclosure.

Adipose Tissue and Type 2 Diabetes

With the growing epidemic of obesity in much of the industrializedcountries, a growing number of human ailments are associated withadipose tissue (i.e., fatty tissue) building up excessively both insideand outside organs, arteries, and other parts of the body. One alarmingstatistic is that the prevalence of obesity in children has increasedfairly dramatically over the last 20 to 30 years. Moreover, theprevalence of type 2 diabetes has also increased rapidly over the last20 years. For example, the incidence of type 2 diabetes in adolescentshas been estimated to increase ten-fold from 1982 to 1994 in the greaterCincinnati area. In addition, a significant number of obese youth haveabnormally severe insulin resistance with an attendant increased risk ofdeveloping type 2 diabetes mellitus. In fact, there is a growingrecognition that visceral or intra-peritoneal fat can be stronglyassociated with insulin resistance and other factors. In one embodiment,the mid-infrared light could be used to melt or damage the visceral orintra-peritoneal fat, thereby potentially reducing the risks associatedwith and incidence of type 2 diabetes in children, adolescences andadults. The mid-infrared light could also be used to render the adiposetissue inactive, in the sense that cytokines are no longer generated byat least some of the adipose tissue.

In humans, adipose tissue is located beneath the skin (subcutaneousfat), around internal organs (visceral fat), and in the bone marrow(yellow bone marrow). Adipose tissue is found in specific locations,which are referred to as ‘adipose depots.’ Adipose tissue containsseveral cell types, with the highest percentage of cells beingadipocytes, which contain fat droplets. In the integumentary system,which includes the skin, adipose accumulates in the deepest level, thesubcutaneous layer, providing insulation from heat and cold. Aroundorgans, it provides protective padding.

Visceral fat or abdominal fat, which is also known as organ fat orintra-abdominal fat, can be located inside the abdominal cavity, packedin between internal organs and torso. The visceral fat is composed ofseveral adipose depots including mesenteric, perigonadal, epididymalwhite adipose tissue and perirenal depots. An excess of visceral fat isknown as central obesity, or “belly fat”, in which the abdomen protrudesexcessively. There is a strong correlation between central obesity andcardiovascular disease. For example, adipose tissue secrete a type ofcytokines (cell-to-cell signaling proteins) called adipokines oradipocytokines, which play a role in obesity-associated complicationsand cardiovascular diseases.

Central obesity is associated with a statistically higher risk of heartdisease, hypertension, insulin resistance and type 2 diabetes mellitus.It is speculated that central obesity predisposes individuals to insulinresistance, and it may also be that the adipokines secreted by abdominalfat may impair glucose tolerance. Insulin resistance is a major featureof type 2 diabetes, and central obesity is correlated with both insulinresistance and type 2 diabetes. For example, increased obesity raisesserum resistin levels, which in turn correlates with insulin resistance.Studies have also confirmed a correlation between resistin levels andtype 2 diabetes.

In one embodiment, a mid-infrared fiber laser could be used to remove ordamage at least some amount of visceral or abdominal fat, therebyreducing the probability of type 2 diabetes and insulin resistance. Theremoval or damage of the adipose can also reduce the cytokines and/orserum resistin secretion or generation, which can also potentiallyreduce some of the type 2 diabetes and cardiovascular complications. Theselectivity of using mid-infrared wavelengths can be valuable, becausethe desire is to remove or damage the adipose without damaging theorgans that are surrounded by the adipose or surrounding blood vessels.For example, it has been contemplated to use a liposuction typetechnique for removing visceral fat. In such a procedure, however,extreme care would be required to avoid damaging or accidentallyremoving parts of the organs below the adipose layers or damaging bloodvessels. Moreover, most laser wavelengths used in medical proceduresusually rely on water absorption, and then transferring the heat to theadipose tissue. Adipose tissue actually has very little water content.Therefore, use of these other laser wavelengths would heat the organtissue or blood, which could lead to damaging the organ tissue or bloodvessels while trying to remove the adipose surrounding the organ.Compared with using liposuction or other laser wavelengths relying in onwater absorption, using lasers at wavelengths where the adipose tissueabsorption exceeds water absorption (e.g., around 1210 nm, 1720 nm or2300 nm) could be advantageous for removing adipose around organs whileminimizing damage to the organs or blood vessels.

In one preferred embodiment, a cascaded Raman oscillator operating near1720 nm may be used to the first overtone band of the fatty acid band(c.f. FIG. 19). In another embodiment, a cascaded oscillator operatingnear 1210 nm or 2300 nm could also be used to remove or damage theadipose tissue. A light source near 3400-3500 nm could also be used,although in this wavelength range has more water absorption, so careshould be taken to avoid water between the laser emission point and theadipose tissue. Although cascaded Raman oscillators are mentioned, otherlasers could also be used consistent with the disclosure. For example,laser diodes, fiber lasers, quantum cascade lasers, solid state lasers,or modelocked lasers could also be used in the therapeutic procedures.

In one preferred embodiment, the mid-infrared laser light can beinjected into the adipose tissue around an organ through a catheter orlaparoscopic device. For example, FIG. 20 illustrates a laparoscopicdevice 2000 that might be used to access the visceral fat depots. Inthis embodiment, three exemplary devices are used: a camera probe forvisualization 2001, 2002, a tweezer system for grabbing or holdingtissue 2003, 2004, and a catheter 2005, 2006 with a light source with afiber 2007 and possibly a suction pipe 2008. The catheter 2005, 2006 caninclude a fiber optic cable to guide the mid-infrared light from thelaser system to the end of the catheter probe, and this fiber should beable to transmit the laser wavelengths. There can also be a lens systemat the end of the fiber optic cable 2007 to collimate or focus the lightat a desired distance from the probe end. The catheter can be guided tothe area of interest in the body using an imaging system, such as anx-ray system or a camera based system. In one embodiment, as shown inFIG. 21, the catheter probe can include a radio opaque tip to helpidentify the catheter location using x-rays. It may be advantageous toalso have a camera system in the catheter, similar to what is usuallyused in endoscopes. That way the operator can watch on an externalmonitor as the fatty tissue is damaged or melted and as the interfacewith the organ surface is reached. In one embodiment where the cathetermay be used with relatively large pockets of fatty tissue, it may alsobe advantageous to have a pipe and vacuum system (e.g., a liposuctionapparatus) to remove the melted or damaged fat from in front of thecatheter. For example, this can avoid the self-limiting of the damage ormelting process, since the fat in front may block further penetration bythe mid-infrared laser light.

Beyond using mid-infrared lasers for visceral fat, there are manyexamples of lipid, adipose, or fat accumulation or growth on the outsideof organs that could also benefit from laser treatment. As anotherexample, there is much clinical data that suggests that obese patientsgrow a layer of adipose tissue around the heart. This epicardial adiposetissue is believed to be responsible for many of the heart ailmentsassociated with obese patients. It is also believed that the body mayreact to the additional adipose tissue or the adipose tissue itself mayemit different chemicals, such as cytokines or macrophages. By usinglaser light near one of the absorption peaks in adipose tissue, theadipose tissue can be damaged or melted. One concern in such a procedureis that the fat is damaged with minimal damage to the heart muscle.Thus, a procedure is desired that melts the fat, but that can bereasonably halted before reaching the heart muscle.

In the case of melting or damaging adipose tissue around the heart, theselectivity of the laser and its wavelength is desirable to distinguishbetween the adipose tissue and the cardiac muscle. Cardiac muscle is atype of involuntary striated muscle found in the walls of the heart,specifically called the myocardium. As an example, the transmission (1minus the absorption in the sample) 2200 through myocardium (heartmuscle) 2201, fatty tissue (adipose) 2202 and aorta 2203 is shown inFIG. 22 (note that the scale is in arbitrary units). As shown in FIG. 7,the fatty tissue has an absorption peak around 1720 nm. FIG. 22 shows,however, that the myocardium 2201 has a local dip in absorption (i.e.,local peak in transmission) between approximately 1600 nm and 1800 nm.Also, most of the dips in the transmission spectra from myocardium 2201and aorta 2203 can be attributed to water absorption bands at 0.97,1.19, 1.45 and 1.94 microns (pointed out by the longer arrows in FIG.22). On the other hand, fatty tissue has different spectral signatureswith dips near 0.93, 1.04, 1.21, 1.39, 1.72, 1.76, 1.92 and 2.14microns, which are indicated by the shorter arrows in FIG. 22.Therefore, selective damage or ablation of fatty tissue 2202 can be donein the wavelength window near 1720 nm, since the myocardium 2201 has alocal minimum in absorption around this range. In one embodiment, thelaser power near 1720 nm can be reduced as the interface between theadipose and the heart muscle is approached. With the difference inabsorption between the adipose and myocardium, the damage to themyocardium can be at least minimized. In another embodiment, it may alsobe desirable to introduce local cooling, so that the heat transfer intothe myocardium tissue from the adipose is also reduced.

Applications in Cardiology for Diagnostics and Therapeutics

As another example, obesity and excess adipose tissue can also lead tomay cardiovascular disorders. For example, atherosclerosis is oneexample of an ailment associated with plaque build-up in the arteries.In 2009, it is estimated that atherosclerosis causes 650,000 deaths inthe US annually, and approximately 17 million deaths worldwide. Mostexisting techniques for examining plaque are based on morphology ofplaques, such as the constriction of the arteries. However, it isestimated that only about 15% of the heart attacks result from plaquethat grows to the point of constricting blood flow.

By using wavelengths in the mid-infrared, particularly wavelengthsbetween about 1.5 microns and 4.5 microns, in one embodiment it may bepossible to perform diagnostics of atherosclerosis by examining chemicalsignatures more so than morphology. To detect so-called vulnerableplaque, the chemical signatures could be used to distinguish normalaorta walls from plaque, even potentially distinguish stable fromunstable plaque.

In one particular embodiment, a mid-infrared SC light source has beenused to perform diagnostic spectroscopy of the constituents ofatherosclerotic plaque. For example, FIG. 17 illustrates some of thedifferences between normal artery 1700 and atherosclerotic plaquebuild-up in an artery 1750. A normal tissue 1700 has smooth muscle cell1701 with an endothelium layer 1702 on the inside of the artery 1700. Inan artery with atherosclerotic plaque 1750, the endothelium layer 1751may be damaged, and there can also be a thin layer of fibrous cap 1752separating the endothelium 1751 from the plaque 1753. Theatherosclerotic plaque 1753 comprises a number of constituents,including smooth muscle cells 1754, active macrophages and foam cells1755 and lipids, calcium and cellular debris. Thus, a normal artery 1700has a different composition than atherosclerotic artery 1750, and thetwo may be distinguished based on different optical absorption spectra.Moreover, light that is selectively absorbed in the lipid-rich plaque1753 may be able to damage the plaque, or at least render it less activein creating bio-chemical reactions in the body.

In one non-limiting example, mid-IR absorption spectra of the componentsof normal artery, which includes endothelial cells 1801 and smoothmuscle cells 1802, are illustrated in FIGS. 18 (a) and (b). As thecompositional elements of the normal artery, endothelial cells 1801 andsmooth muscle cells 1802 exhibit similar absorption features in the2.6-3.8 μm wavelength range. A broad absorption feature ranging from2.8-3.2 μm and peaking at ˜3050 nm is observed, and this can beattributed to the vibrational bands of O—H stretching in the hydroxylgroup and N—H stretching present in the protein amino acids.

The absorption spectra for some of the constituents of plaque, includingmacrophages 1803, adipose tissue 1804, and foam cells 1805 areillustrated in FIGS. 18 (c), (d) and (e). In the lipid-rich samples,including adipose tissue 1804 and foam cells 1805, the individualabsorption lines can be distinguished in the 3.2-3.6 μm windows, e.g.═CH stretching vibration at ˜3330 nm, CH₃ stretching vibration at ˜3390nm, and CH₂ stretching vibration at ˜3420 nm and ˜3510 nm. In addition,while the macrophages 1803 exhibit a similar absorption spectrum ascompared to the normal artery cells 1801 and 1802, prominent spectralcharacters between ˜3.2 to 3.6 μm with two absorption peaks at ˜3420 nmand ˜3510 nm are observed in the macrophages-transformed foam cells 1805and adipose tissue 1804 absorption spectra. Such spectral pattern mayarise from the absorptions of hydrocarbon chains, e.g. CH₂ and CH₃bonds, present in both the fatty acids and cholesterol esters, both ofwhich fall in the adipose tissue category. Therefore, the spectraldifference between the macrophages 1803 and foam cells 1805 isconsistent with the pathological relationship between these two celltypes, i.e. macrophages engulf lipid-rich substances to become foamcells.

To further investigate the composition properties of the constituents ofplaque, the absorption spectrum has been measured of egg yolk 1901,which is considered to be a conventional composite model of atherogeniclipoprotein. The spectral character of egg yolk 1901 (FIG. 19), sharesmany similarities with that of foam cells 1805 (see FIG. 18 (e)).Compared to endothelial cells 1902 and smooth muscle cells 1802, whichform the normal artery, egg yolk 1901 shows distinct lipid-richabsorption features in 3.2-3.6 μm wavelength range while havingcomparable absorptions in the 2.8-3.2 μm O—H and N—H vibrational bands.

Although the example of FIGS. 18 and 19 show that a large absorptionpeak can be observable from adipose tissue between approximately 3400 to3500 nm, one problem with performing diagnostic in this wavelength rangeis that the water and blood absorption can be very strong (in thiswavelength range, the absorption for blood and water are approximatelyequal). For instance, at 3400 nm the water absorption is approximately700 cm⁻¹, and even at 3500 nm the water absorption is about 334 cm⁻¹.Therefore, it might be difficult to perform spectroscopy of theatherosclerotic plaque without either putting the probe directly incontact with the endothelium layer or pausing the blood and water flowthrough the artery.

In a preferred embodiment, the diagnostics or spectroscopy of the plaquecan be performed in the first overtone wavelength range, for example inthe wavelength range between 1300 and 1900 nm, more preferably in thewavelength range between 1700 nm and 1750 nm. Similar to FIGS. 18 and19, spectral features will be observable in this first overtone window,but one advantage can be that the water and blood absorption may beconsiderably weaker. For example, the water absorption coefficient at1700 nm is about 5.15 cm⁻¹, while at 1750 nm the absorption coefficientis approximately 6.4 cm⁻¹. The lower water and blood absorption can makeit more likely to perform spectroscopy in this wavelength range.

As another embodiment of diagnostics or spectroscopy in cardiovascularmedicine, broadband sources in the mid-IR can also be used withabdominal aortic aneurysms (AAA). An abdominal aortic aneurysm isexemplary when the large blood vessel that supplies blood to theabdomen, pelvis and legs becomes abnormally large or balloons outward.The type of plaque considered most vulnerable to disruption is athin-capped fibroatheroma with increased inflammatory cell content. Athin-capped fibroatheroma typically has a cap thickness of less than 100microns and a lipid core accounting for greater than 40% of the plaque'stotal volume. Plaque rupture is among the most frequent type of plaquecomplication, accounting for an excess of 70% of fatal acute myocardialinfarctions and sudden coronary deaths.

Collagen and elastin are major structural components of vessel wallsthat have been widely implicated in aneurysm formation, progression andrupture. For example, the most prevalent structural modificationassociated with human AAA's that has been reported is a reduction inelastin concentration in the aortic wall. Also, increased collagenconcentration is another matrix modification that has been widelyobserved in human AAA's. It can be noted that Collagens I and III arethe principal collagen components of the aorta. The mid-infrared spectrafor collagens and elastins are illustrated in FIG. 7, and changes in theoptical spectra could be used to potentially diagnose the presence ofplaque and changes associated with AAA in the aorta walls. For example,as the ratio of collagen to elastin changes, the optical spectrum in thewavelength range above 1000 nm will also change. In a preferredembodiment, the optical spectrum between 1400 nm and 1800 nm can bemeasured, and changes in the spectral shapes can be correlated with theratio of collagen to elastin. For example, spectral fingerprinting orsome sort of principal component analysis can be performed onabsorption, transmission or reflection data to distinguish betweendifferent ratios of collagen and elastin.

As yet another example of using light from SC sources for diagnostics,SC light in the near-infrared can be used to screen for or diagnosecolorectal cancer or pancreatic cancer. Colorectal cancer is the fourthmost common form of cancer in the U.S. and the third leading cause ofcancer-related death in the Western world. One area in need ofimprovement is accuracy in detection of flat polyps, or fat dysplasiathat does not necessarily protrude out of the mucosa. Whereasadenomatous polyps can readily be detected visually using the fiberoptic and CCD cameras in endoscopes, flat polyps can be missed, thusincreasing the risk of colorectal cancer despite early screening.Moreover, there are diseases such as ulcerative colitis, which is a formof inflammatory bowel disease that do not lead to the outgrowth ofpolyps. If this disease is suspected, the only diagnostic is to acquiremany biopsy samples. Therefore, a technique is required for detectingflat polyps based on their chemical or compositional signatures todistinguish normal mucosa from cancerous tissue.

Colorectal cancer can be distinguished from the normal mucosa byexamining the chemical differences in tissue composition usingreflection spectroscopy in the near-infrared wavelength range. Thedifferences in tissue composition between colorectal cancer and normaltissues have been extensively analyzed using chemical, histochemical,biochemical and immunohistochemical studies. It has been shown thatadenoma and carcinoma of colorectal tissues have altered compositions infatty acids, carbohydrates, glycosaminoglycans, glycoproteins andglycolipids. In particular, the lipid near-infrared absorption bandsprovide diagnostic markers useful for colorectal and pancreatic cancerdiagnosis. More specifically, due to the rapid proliferation ofcancerous cells, there is reduced lipid content in adenoma and carcinomacolorectal tissues.

Prior studies have looked for the missing lipid lines throughspectroscopy either in the mid-infrared (e.g., 2000 to 5000 nm) ornear-infrared (e.g., 1600 to 1800 nm). The mid-infrared light showsstrong signals at the fundamental absorption bands, but the waterabsorption is much stronger and prevents imaging in a realisticendoscopic setting. In contrast, although absorption changes are smallerin the near-infrared wavelength range, the near-infrared light cantransmit through water. Moreover, near-infrared spectroscopy can usestandard glass fiber used in the telecommunications industry, whichmakes it much simpler to transport through the endoscope by addition ofa fiber or a bundle of fibers.

In one embodiment, a screen for colorectal cancer may be achieved byadding to an endoscope or a colonoscopy device fibers for reflectionspectroscopy in the near-infrared wavelength range. In one embodiment,one or more fibers may be used for illuminating the sample, and then oneor more fibers may be used for capturing the reflected signal andbringing back through the endoscope. At the end of the illuminationfiber, mirrors or lens may be used to focus or collimate light onto thewalls of the colon or large intestines. In a particular example, theillumination and return fibers may form a fiber bundle. In anotherexample, the same fiber may be used for illumination and return of thesignal. Once the reflected signal is transported back through theendoscope, the signal can be analyzed using a series of detectors or aspectrometer followed by one or more detectors. For example, an opticalspectrum analyzer might be used to look at the signal strength as afunction of wavelength.

In a particular embodiment, the spectroscopy can be convenientlyperformed using a near-infrared SC laser such as in FIG. 12 that cangenerate light between 1600 and 1800 nm, a wavelength window withmultiple C—H first overtone absorption lines and a minimum in waterabsorption and scattering. With the broadband light, spectralfingerprinting can be performed for inspection of the lipid lines, andthe sensitivity can be improved by taking the derivative of thereflected light as a function of wavelength. For example, the SC lasercan be coupled to a transmission or illumination fiber, which is used totransport the light from the SC laser to the end of the endoscope forsample inspection. The output from the fiber-based SC laser can beconveniently coupled to a fiber, and a separate fiber is used forillumination any contamination from the endoscope or sample does notaffect the SC laser. This permits, for example, the illumination andreflected sample fibers to be used on a patient and then discarded.

As an example, the first overtone of the lipid absorption lines fall inthe near-infrared, and vibrational spectroscopy shows weaker butdistinct changes between 1670 and 1790 nm. In particular, normal tissuecan show distinct lipid lines, but the lines reduce in strength forcancerous tissue. For instance, FIG. 23 illustrates the changes in thenear-infrared reflection data between normal 2301 and cancerous 2302pancreatic tissue, and between normal 2303 and cancerous 2304 colorectaltissue. The differences can be further enhanced by taking a derivativeof the data. For instance, for pancreatic tissue the derivatives fornormal 2305 and cancerous 2306 tissue are shown, while for colorectaltissue the derivatives for normal 2307 and cancerous 2308 tissue areshow. In one embodiment for colorectal cancer, the inset 2309 overlaysthe derivative data between approximately 1670 nm and 1790 nm for normal2311 and cancerous tissue 2310. Moreover, the inset 2302 showsderivative spectra for colorectal cancer for different degrees ofprogress toward cancer. In this example, the normal tissue spectrum is2313, the cancerous tissue spectrum is 2314, and different curves inbetween represent different degrees of progress toward a cancerousstate. Thus, for the case of colorectal or pancreatic cancer in thisexample, the spectral signature falls within a minimum in waterscattering and absorption from FIG. 6 or 7, so the spectral data shouldbe observable through a colonoscopy procedure.

Spectroscopy, similar to that of FIGS. 18 and 19 in either thefundamental wavelength window between 2600 nm and 3800 nm or the firstovertone can be performed using supercontinuum lasers based on fibers.For spectroscopy in the fundamental range around 2600-3800 nm, aZBLAN-fiber based SC source can be used. On the other hand, forspectroscopy in the first overtone window between approximately 1400 and1800 nm, a fused-silica or high-nonlinearity fiber based SC source canbe used. Alternatively, other broadband lasers with the appropriatewavelength ranges can also be used. In one embodiment, the SC laserlight can be coupled to a catheter, which can then be inserted into theartery to perform the diagnostic spectroscopy. In one preferredembodiment, to inspect for plaque inside an artery, a periscope-typecatheter that can be rotated approximately 360 degrees may be required.

In one preferred embodiment, absorption or reflection spectroscopy couldbe performed by coupling the SC light into a catheter 2100 designedusing primarily reflective optics. One advantage of using reflectiveoptics is that it can be broadband, and, therefore, be compatible withSC light. As an example, FIG. 21 illustrates a single-mode ZBLAN fiber2101 based endoscopic catheter 2100 that uses achromatic reflectiveoptics 2102 and allows noncontact measurement. If wavelengths beyond 2.5microns are used, then mid-infrared fibers, such as ZBLAN, tellurite,fluorides or chalcogenides, can be used advantageously in the probe. Ifwavelengths shorter than 2.5 microns are used, then the single-modefiber can be made out of more standard material, such as fused silica.In addition, a radio opaque tip 2104 could be installed in the front endof the catheter 2100 for the position guidance. For instance, x-ray orsome other type of imaging system could be used to monitor the positionof the catheter tip 2104 and to guide it to the desired location in thebody.

The catheter of FIG. 21 comprises at least three main components, i.e. asingle mode fiber 2101, a 90 degree off-axis micro concave mirror 2102,and a rotational micro-motor 2103. In this embodiment, the mid-IR lightemitting from the angle-cleaved fiber tip 2105 can be first re-directedby 90 degrees and collimated by the concave mirror 2102. If it isdesired to confine the collimated beam diameter to the order of ˜100-200μm, the radius curvature of the micro concave mirror could be ˜250 μm.In one embodiment, the micro-mirrors could be fabricated and implementedby MEMS techniques on silicon substrate with gold coating. The concavemirror 2102 could be mounted onto a 1 mm diameter rotational micro-motorto enable the 360-degree peripheral optical scan. As an example, theminiature catheter of FIG. 21, which could also be disposable, with anouter diameter of ˜1 mm could be mechanically coupled to the outputpigtail of a SC laser to construct an integrated, minimally invasive invivo reflective absorption spectroscopy and laser ablation system.Although one example is provided of a catheter probe 2100, other designscould be used consistent with the elements of this disclosure. Forexample, other mid-IR catheters include hollow glass waveguidecatheters, germanium oxide fiber catheters, or catheters employing largecore multimode fibers.

Beyond reflection or absorption spectroscopy, other types of opticalmeasurements can also be used. In one non-limiting example, aninterferometric system can be used to measure thickness of variouselements, thereby providing morphological information in addition tochemical composition information. For instance, an optical coherencetomography system, which is basically a Michelson interferometer, can beused with the SC light source to measure the thickness of the fibrouscap. As described above, when the fibrous cap becomes thinner than about100 microns, there is an increased risk of rupture. More particularly, afibrous cap thickness of order of 65 microns is considered to be of highrisk, potentially being in the category of so-called vulnerable plaque.

To perform therapeutic procedures, it may be more desirable to usenarrower-band, higher power (or higher spectral density) lasers. Forexample, to perform the diagnostics or spectroscopy, a broadband laseris advantageous, and a supercontinuum light source is one example of aconvenient light source. On the other hand, for therapeutics, where thedesire may be to damage selectively on or more compositional elements,it may be more desirable to use a narrower band, higher power lightsource such as a cascaded Raman oscillator. As an illustration, onetherapeutic procedure may be to damage selectively the lipid-rich plaquecore lying under the endothelium and fibrous cap (FIG. 17). In onepreferred embodiment, a cascaded Raman oscillator operating near 1720 nmmay be used to the first overtone band of the fatty acid band (c.f. FIG.19). A light source near 3400-3500 nm could also be used, although inthis wavelength range has more water absorption, so care should be takento avoid water between the laser emission point and the plaque. Althoughcascaded Raman oscillators are mentioned, other lasers could also beused consistent with the disclosure. For example, laser diodes, fiberlasers, thulium-doped fiber lasers, quantum cascade lasers, solid statelasers, or modelocked lasers could also be used in the therapeuticprocedures.

Although the above discussion has described one example of using themid-infrared laser light in cardiovascular organs, there are many othersituations where the laser procedure can be beneficial by selectivelyabsorbing in adipose, collagen or elastin. In yet another embodiment,there is a growing need for percutaneous valve replacement, for examplewith the aortic or pulmonary valves. When an artificial stent or valveis placed in the body, it may also be desirable for the collagen tocross-link and secure the stent or valve in place. By using mid-infraredlight near the stent or valve, collagen contraction can occur locally,and the heat generated in the collagen can also promote collagencross-linking. There may be a further advantage of also heating theelastin locally in the vicinity of the stent or valve.

In yet another embodiment, the mid-infrared laser light could be used tominimize collateral damage for procedures in the brain. For example,mid-infrared laser light could be used for selective laser ablation forremoving tissue obstructions in shunt catheters used in hydrocephalus.Hydrocephalus is defined as an excessive accumulation of cerebrospinalfluid (CSF) within the cavities of the brain known as ventricles.Hydrocephalus is one of the more common childhood brain disorders, withan incidence as high as 1/500 births. Hydrocephalus is usually alifelong condition, and the standard treatment involves divertingventricular CSF through a surgically implanted silicone catheter with apressure-controlled valve (shunt) into the abdominal cavity, where it isreabsorbed along the belly wall. The number one problem of the shunt isblockage due to tissue growing into the drainage holes, which line theside of the silicone tube. Because of the side placement of the drainageholes, it is virtually impossible to clear the blockage mechanically.Moreover, the same blockage problem is common to any catheter implantedin the body, such as those also used to deliver drugs along the spinalcord or drain abscesses.

As an example, using the mid-infrared light a fiber-based “rotor-rooter”can be implemented to clear the blockage in the shunts by using theselective absorption in the blockage material versus silicone rubbershunts. In fact, silicone rubber can be fairly transparent out towavelengths longer than 8.58 microns. Standard fiber with 125 microncladding and 250 micron diameter with coating should easily fit withinmost of the shunts, which are typically 1-2 mm inner diameter. Moreover,the end of the fiber can be etched or cleaved to emit light at 45degrees, enabling light delivery to the drainage holes. In oneembodiment, a tip design similar to FIG. 21 could be used. Byselectively ablating the tissue blocking the shunt drainage holes, theblockage can be removed without requiring surgical removal of the shuntand without damaging the walls of the shunt. It is desirable also not todamage brain tissue just outside the drainage holes.

As yet another example, the mid-infrared light could be used to detectcancerous tumors in the brain. In particular, brain tissue ischaracterized by high lipid content. The amount of lipids decreases, andits composition changes in the most frequent primary brain tumor, theglioma. For example, spectroscopy of brain tissue has shown that gliomasare characterized by increased water content and decreased lipidcontent. Based on the different spectra from lipids and water, such asshown in FIGS. 6 and 7, spectral changes should be present for gliomasversus normal brain tissue. In one embodiment, a fiber probe could beinserted into suspect areas of the brain, and light from the braintissue could be reflected (potentially transmitted, if, for example, twoprobes are used) to perform reflection spectroscopy. The light could befrom a super-continuum fiber laser operating in the range ofapproximately 1600 to 1800 nm, and the reflected light could be analyzedusing a spectrometer. The changes in spectra could also be enhanced bytaking a derivative of the reflection data as a function of wavelength.Reflection data from different parts of the brain tissue could becompared. As an example, the normal brain tissue should have lipid linesin the spectra, while the glioma regions should have reduced lipid linesand enhanced water lines. By performing such differential spectroscopy,the boundary between normal and tumor brain tissue could be betterdemarcated.

Beyond detecting cancerous regions in the brain or central nervoussystem, mid-infrared light could also be used to cut brain or centralnervous system tissue with minimal collateral damage. The precise cutscould be achieved by tuning into lipid lines, and then cutting tissuethat is lipid rich. In contrast, many laser cutting procedures rely onabsorption in water. First, relying on water can be non-selective, sincemost tissue has significant water content. Second, as the water in cellsis heated, the water in the cells expands as it turns to vapor, causingthe cells to rupture. Consequently, water-based heating can lead tosignificant collateral damage in the surrounding tissue, which would beparticularly undesirable for operation in brain tissue or nervous systemtissue.

In one embodiment, more precise cuts for tissue of the central nervoussystem or brain tissue could be accomplished by using a laser tuned near1720 nm or one of the other wavelength peaks in adipose absorption. Asan example, myelin is a dielectric material that forms a layer, theso-called myelin sheath, usually around the axon of a neuron. Myelinmade by different cell types varies in chemical composition andconfiguration, but it still performs the same kind of insulatingfunction. Myelinated axons are white in appearance, hence the term“white matter” of the brain. In particular, myelin is composed of about80% lipid and about 20% protein. As a consequence, a laser tuned to oneof the lipid absorption peaks (FIGS. 6 and 7) could be used to cutmyelin regions of the brain or central nervous system with higherprecision than a laser tuned to a water line. For example, a fiber couldbe directed to the region of interest for performing the cut in thetissue. Then, using a cascaded Raman wavelength shifter that emits lightnear 1720 nm, the light could be used to heat the adipose-rich tissueand provide a clean cut. There should result less damage to thesurrounding tissue with less lipid content, resulting in less collateraldamage. As an alternative, it may also be desirable to use anotherwavelength tuned to adipose, such as wavelengths near 2300 nm (c.f. FIG.7). Because of the higher absorption near the 2300 nm wavelength, thepenetration depth can be less, leading again to a more precise cut. Thisis just one example of accomplishing a clean cut based on tuning to oneof the absorption resonances of particular tissue types, such asadipose, collagen or elastin. There are many other parts of the bodywhich can benefit from the precise cuts beyond the brain.

Described herein are just some examples of the beneficial use ofmid-infrared laser treatment based on the selective absorption inadipose, collagen and elastin. However, many other medical procedurescan use the mid-infrared light consistent with this disclosure and areintended to be covered by the disclosure.

Some features of at least some examples of embodiments of the inventionare as follows:

-   -   1. catheter based procedure for treatment of obesity related        ailments        -   a. laser light selectively absorbed in adipose tissue            surrounding internal organs, wherein the wavelength of the            laser light coincides approximately with a local maximum in            absorption in adipose        -   b. local minimum in loss from water absorption and            scattering in tissue        -   c. operate at eye safe wavelengths, operate at wavelength            near 1720 nm        -   d. light is generated by a fiber laser pumped by laser            diodes        -   e. catheter includes fiber optic cable capable of            transmitting the light and piping to remove adipose damaged            in procedure    -   2. fiber laser is a thulium-doped fiber laser or an erbium-doped        fiber laser followed by a cascaded Raman wavelength shifter    -   3. remove or damage adipose without substantially damaging        tissue of organ    -   4. visceral fat, intra-peritoneal fat, and abdominal fat    -   5. fat associated with ailments associated with type 2 diabetes        or cardiovascular ailments or diseases    -   6. local cooling to localize damage    -   7. damage to adipose tissue results in reduction or stopping of        cytokines and other chemicals being emitted by adipose tissue    -   8. catheter also includes lens system, imaging system, camera        system    -   9. light based procedure for treatment of obesity related        ailments        -   a. laser light selectively absorbed in adipose tissue            surrounding internal organs, wherein the wavelength of the            laser light coincides approximately with a local maximum in            absorption in adipose        -   b. local minimum in loss from water absorption and            scattering in tissue        -   c. remove or damage adipose without substantially damaging            tissue of organ        -   d. damage to adipose tissue results in reduction or stopping            of cytokines and other chemicals being emitted by adipose            tissue    -   10. visceral fat, intra-peritoneal fat, and abdominal fat, fat        associated with ailments associated with type 2 diabetes or        cardiovascular ailments or diseases    -   11. organ is heart, and adipose tissue is damaged without        substantial damage to myocardium and smooth muscle cells    -   12. laser wavelength is approximately 1720 nm in the eye safe        zone    -   13. light is generated by a fiber laser pumped by laser diodes    -   14. (13+) fiber laser is a thulium-doped fiber laser or an        erbium-doped fiber laser followed by a cascaded Raman wavelength        shifter    -   15. catheter used for percutaneous procedure, catheter includes        fiber optic for delivering mid-infrared light, imaging or camera        system, and suction means for removing damaged adipose tissue    -   16. catheter based procedure for treatment of obesity related        ailments        -   a. laser light selectively absorbed in adipose tissue            surrounding internal organs, wherein the wavelength of the            laser light coincides approximately with a local maximum in            absorption in adipose as well as approximately local maximum            in absorption for collagen and elastin        -   b. local minimum in loss from water absorption and            scattering in tissue        -   c. operate at eye safe wavelengths, operate at wavelength            near 1720 nm        -   d. remove or damage adipose without substantially damaging            tissue of organ        -   e. catheter includes fiber optic cable capable of            transmitting the light and piping to remove adipose damaged            in procedure    -   17. light is generated by a fiber laser pumped by laser diodes,        fiber laser is a thulium-doped fiber laser or an erbium-doped        fiber laser followed by a cascaded Raman wavelength shifter    -   18. damage to adipose tissue results in reduction or stopping of        cytokines and other chemicals being emitted by adipose tissue    -   19. visceral fat, intra-peritoneal fat, and abdominal fat, fat        associated with ailments associated with type 2 diabetes or        cardiovascular ailments or diseases    -   20. organ is heart, and adipose tissue is damaged without        substantial damage to myocardium and smooth muscle cells.

There are preferred embodiments in which the mid-infrared laser lightmay need to be delivered within a patient to perform a therapeutic ordiagnostic procedure. For example, the mid-infrared laser light can bedelivered with a fiber or light-pipe that is housed within a catheter orlaparoscopic device. In one non-limiting example, consider themid-infrared light being directed into an artery using a catheterdevice. In a preferred embodiment, the catheter may comprise a fiber todeliver or guide the light to its intended destination. The catheterfiber can be coupled using a coupler or a mechanical splice to theoutput of the mid-infrared laser. Having a separate fiber in thecatheter that can be connected or dis-connected from the mid-infraredlaser has a number of benefits. For instance, the mid-infrared laser canavoid any damage incurred when the catheter flexes as it passes throughthe patient. Also, the fiber in the catheter could be disposable,thereby avoiding contamination from one patient to another. Finally,there is an economic benefit to the catheter and laser maker, who cansell a separate catheter fiber per procedure used.

The fiber used within the catheter should transmit a significantfraction of the laser energy at the laser wavelength of the mid-infraredlight of interest. As an example, if the mid-infrared wavelength ofinterest is at or near 1720 nm, then the catheter fiber can be made fromfused silica. More generally, for wavelengths shorter than ˜2.5 microns,a fused-silica based single-mode, multi-mode, photonic crystal fiber, orlight guide can be used. For longer wavelengths, other mid-infraredfibers may be used, such as fibers made from various fluoride,chalcogenide, or tellurite compositions.

In addition to the fiber, the catheter may also comprise collimating orfocusing optical elements. For wavelengths shorter than ˜2.5 microns,quartz or fused silica lenses may be used. For longer wavelengths, itmay be advantageous to have lenses made from other material, such ascalcium fluoride, zinc sulfide, chalcogenide, etc. Alternatively, curvedmirrors may be used that have a reflective metal coating or dielectriccoating that substantially reflects the wavelengths of interest.

In one embodiment, the catheter comprising the fiber can be adapted tobe inserted into a patient's body through the femoral artery in apatient's leg or thigh. As in a catheterization laboratory procedure,the catheter may be inserted into a larger artery, and various wires,light pipes or fibers, and other devices can be inserted through thebody via the catheter that is inside the artery. Then, the catheter canbe guided through the aorta to different parts of the cardiovascularsystem, including for instance the heart, the renal arteries, or theright atrium (through the inferior vena cava).

As illustrated in FIG. 21, the catheter 2100 may have a radio opaque tip2104, which permits a physician to guide the catheter 2100 through thebody using an x-ray imaging system. Alternately, dyes, fluorescentmaterials, or other imaging systems can be used to track the location ofthe catheter as it is inserted into the body. Moreover, dyes,fluorescent materials and/or other imaging systems can also be used toestimate or measure the dimension of the artery or other blood vessel.Alternately, an ultrasound or laser radar type system (e.g., an echosystem) may be used to estimate or measure the inner and/or outerdimension of the artery or other blood vessel. For the catheter tosafely travel through the arteries, the outer dimensions of the cathetermay in one instance be less than 2 to 2.5 mm outside diameter (e.g., 6or 7 French gauge). In other applications, catheters smaller than about1-1.5 mm may be desirable; e.g., when the catheters are to be fedthrough arteries in the arm or wrist. On the other hand, forapplications in the main aorta or leg or thigh arteries, largercatheters with outer diameters ranging from approximately 2.5 to 10 mmmay be used. Any of the catheter designs in this disclosure may be usedwith the catheters of smaller or larger dimensions.

In a preferred embodiment, the catheter such as the catheter 2100 may beguided along the length of an artery, and the mid-infrared light may becollimated or focused onto the artery walls to perform a therapeutic ordiagnostic procedure. In one embodiment, the laser light from the fiber2101 may be turned by approximately 90 degrees to collimate or focusonto the artery walls. For instance, FIG. 21 illustrates that a curvedmirror 2102 after the fiber output 2105 may be used in the catheter 2100to turn the light and collimate or focus the light. Therefore, thecatheter not only comprises the fiber optic cable or light pipe 2101,but it may in addition comprise optical element 2102 for turning thelight and collimating or focusing the light.

As an example, FIG. 24 illustrates the cross-section of a renal artery2400 (off-shoot artery from the aorta, leading to the kidneys). In thisexample, the radius 2401 from the center of the artery to the outside ofthe artery wall is approximately 3 to 3.5 mm. In this figure, the arterywall comprises (from inside to outside) layers of endothelium 2402,media 2403 comprising mostly smooth muscle cells, adventitia 2404, and afat or lipid layer 2405. Within the adventitia 2404 and fat 2405 layerare also contained renal nerves 2406. The thickness of the wall of theartery 2400 is this instance is about 1 to 1.5 mm. To avoid damage tothe artery 2400 when inserting a catheter, as mentioned earlier, thecatheter size should be less than approximately 2 to 2.5 mm outerdiameter. Although one embodiment of a renal artery is shown in FIG. 24,it should be understood that the diameter of the artery varies betweendifferent locations in the body as well as between different patients.

As a consequence of the different sizes of arteries and wallthicknesses, it is advantageous if the catheter containing the fiber canbe adjusted to focus the light to different levels of depth. Then, thephysician or medical professional can adjust the focal distance toaccommodate different patients and different parts of the body. As willbe described below, there are at least three ways to accomplish anadjustable focal distance. First, the distance from the fiber to thecurved mirror or lens can be varied to change the focal distance. Thiscan be accomplished in one embodiment by moving the fiber end back andforth along the length of the catheter. Second, the radius of curvatureof the curved mirror can be varied to change the focal distance. Thiscan be accomplished in a preferred embodiment if the curved mirror ismade of micro-electro-mechanical system (MEMS) mirrors or if the curvedmirror is a deformable reflective surface. Third, in another embodimentof a multi-element focusing system, the distance between differentfocusing optical elements can be varied to change the focal distance.These adjustments can be done manually via a manual actuator or anautomatic actuator under control of a computer, an electrical system, ora controller. In one embodiment, the distance of the fiber to theturning mirror can be adjusted using a micrometer-type screw, aninch-worm turning motor or a stepping motor. In another embodiment,there can be an electrical control voltage applied to MEMS or deformablecurved mirrors.

In one embodiment, the adjustability of the focal distance and the focalspot size can be illustrated using the design shown in FIG. 21 using acurved mirror 2102 to collimate or focus the light at 90 degrees to thefiber end 2105. FIG. 21 illustrates that the end of the fiber 2105 canbe cut angle cleaved to prevent feedback into the mid-infrared laserfrom the fiber end. Alternatively, the end of the fiber 2105 can beanti-reflection coated. Neither may be necessary if the laser isinsensitive to a few percent reflections, or if an isolator is usedafter the mid-infrared laser. It may be advantageous to also have acamera system in the catheter 2100, similar to what is usually used inendoscopes. In one non-limiting example, the same fiber 2101 can be usedto carry the camera signal as the mid-infrared light. Alternatively, oneor more separate fibers can be used for the camera and illuminationsystem separate from the fiber or light pipe 2101 delivering themid-infrared light. In a preferred embodiment shown in FIG. 21, amicro-motor 2103 may be used to rotate the mirror 2102, so that thelight can hit different circumferentially spaced positions on the arterywalls. Alternatively, the operator or physician can rotate the overallcatheter 2100 to change its location or angle. Moreover, the catheter2100 outer diameter can be less than 2 to 2.5 mm, and a window can beused after the curved mirror to transmit the light to the appropriatelocation on the artery wall. Finally, as previously described, a radioopaque tip 2104 may be used to monitor the location of the catheter,particularly as it is inserted or drawn back out.

A curved mirror 2102, such as a parabolic or spherical mirror, can beused to turn the light by 90 degrees as well as to collimate or focusthe light. In some embodiments, a turn mirror or prism can be used inaddition to a lens to focus or collimate the light. One advantage of thecurved mirror 2102 is that a single element may be used to turn thelight and collimate it and focus it, instead of the two elements usedwhen using a lens. Another advantage of a curved mirror 2102 is that itcan accommodate a wide range of wavelengths, since reflective optics(i.e., mirrors) are less susceptible to chromatic changes thanrefractive optics (i.e., lenses). For example, chromatic aberrations canarise when using broadband light with refractive optics because theindex-of-refraction (and, hence, focus length) changes with wavelength.On the other hand, a curved mirror may introduce beam distortions suchas coma onto the beam.

To illustrate the properties of a curved mirror embodiment, a ZEMAXsimulation program has been used to calculate the adjustability of thefocal length in the curved mirror case. In the simulations provided inthe remainder of the disclosure I assume that the fiber is a standardsingle-mode fiber with a numerical aperture of 0.14 and a core sizeranging from 8-10 microns. Although these parameters are selected forthe simulations, single mode fibers may have a numerical aperturebetween about 0.05 and 0.2 and core diameters ranging in size from about2 to 25 microns or more. For this set of simulations, it is assumed thata 90 degree parabolic mirror is used, and that a focused beam is desiredabout 1 to 1.5 mm or more depth into the artery wall. FIG. 25illustrates the simulation conditions, where the fiber distance 2501 isdefined from the end of the fiber core 2502 to the center of the curvedmirror 2503, and the focal distance 2504 is defined from the center ofthe mirror 2503 to the location of the focus 2505. The fiber distance2501 can be varied exemplary by moving the fiber back and forth withrespect to the curved mirror, either manually, using inch worms ormicrometers, or stepper motors.

For this embodiment, the calculated results are shown in FIG. 26 a,which plots 2601 the focal distance from the mirror versus the fiberdistance from the mirror for an assumed radius of curvature of 2.2 mm.As shown, the focal distance can be varied from about 2 mm to greaterthan 7 mm by changing the fiber distance from 10 mm down to about 3 mm.For the single parabolic curved mirror and 90 degree turn, FIG. 26 bplots the focal distance versus root mean square, RMS, spot radius alongthe x-axis 2602 and the y-axis 2603. In this case, the x- and y-axisresults are different, indicating a potential aberration such as coma.To further illustrate the beam shape, FIG. 27 provides spot diagrams atdifferent focal distances for the cases circled in FIG. 26 a (2701corresponds to 2604, 2702 corresponds to 2605, and 2703 corresponds to2606).

In the configuration similar to FIG. 21 or FIG. 25, an alternativeembodiment provides a way to vary the focal distance 2504 by varying theradius of curvature of the curved mirror 2102 or 2503. FIG. 28 shows twoparticular embodiments of adaptive optics techniques in which the radiusof curvature can be adjustable. In FIG. 28 a, the curved mirror can bemade of a series or three dimensional array of MEMS micro-mirrors 2801,each of which could be rotated and/or moved up and down, preferably inan analog fashion. The plurality of MEMS mirrors are reflective and mayalso be coupled to a conductive element, and the MEMS mirrors can befabricated on one or more semiconductor substrates 2802. Above the oneor more substrates and below the plurality of mirrors can be one or moreelectrodes 2803. Thus, the micro-mirrors can be adjusted by changing thevoltage between the conductor coupled to the mirrors and the electrodes.By using the series or array of MEMS mirrors, different radius ofcurvature mirrors can be piecewise constructed.

In an alternative embodiment, the radius of curvature can be adjusted byusing a deformable mirror reflective surface 2850 (FIG. 28 b). Thedeformable mirror surface 2851 may also have a conductive layer 2852.The deformable mirror 2851 may be supported above one or moresemiconductor substrates, and on the substrates may be grown or attacheda plurality of electrodes 2853. By varying the voltage applied to theplurality of electrodes 2853, the shape or radius of curvature of thedeformable mirror may be adjusted. Although FIG. 28 illustrates two waysof altering the radius of curvature, other methods may also be used andare intended to be covered by this disclosure.

ZEMAX simulations were also conducted for the different radius ofcurvature mirrors in the configuration of FIG. 25. For example, theresults are shown in FIG. 29 assuming that the fiber end is kept 5 mmfrom the mirror center. FIG. 29 a shows how the focal distance from themirror varies 2901 with different radius of curvature for the mirror.For instance, changing the radius from 1.5 mm to 2.75 mm changes thefocal distance from 2 mm to about 5 mm. The circled point 2903corresponds to the condition used in FIGS. 26 and 27. As the radius ofcurvature and the focal distance is changed, the beam radius at thefocus 2902 also changes (FIG. 29 b). The geometric beam radius isplotted in FIG. 29 b, which corresponds to the distance of the farthestray from a reference point. Although these simulations are performedassuming a parabolic mirror shape, other curved mirror shapes can beused and are also intended to be covered by this disclosure.

Despite the simplicity of the single curved mirror configuration of FIG.21 or 25, beam distortion between one axis and the other may be alimitation. If a symmetric beam is desired, then an alternate embodimentmay be used with a flat turn mirror followed by a lens. Although thiswould appear to have two optical elements, the lens could also serve asa window for the catheter housing. As an illustration, thisconfiguration 3000 is simulated using ZEMAX for the parameters definedin FIG. 30. The fiber end 3005 is a distance 3003 from the center of aflat mirror 3001, which serves to turn the beam by 90 degrees. Then, alens is placed at the catheter wall, so it can also serve as the windowfor the light beam to emerge. The focal distance 3004 is defined as thedistance from the center of the flat mirror 3001 to the minimum beamwaist location 3006. The lens 3002 has a radius of curvature R, wherefor a lens the radius of curvature is equal to twice the focal length ofthe lens (R=2f).

To select the appropriate radius of curvature or focal length of thelens, FIG. 31 plots the focal distance from the mirror 3101 andgeometric beam radius at the focus 3102 versus the radius of curvatureof the lens, assuming that the fiber is kept 2.5 mm from the mirrorcenter. In one embodiment, 3103 corresponds to a focal distance of ˜3.8mm at a radius of curvature of 1.5 mm. It should be noted that the lenscan in another embodiment be made to be adjustable in radius ofcurvature. In one embodiment, a liquid filled lens can be used, and theradius can be changed by changing the amount of liquid or the liquidpressure. Alternately, if the lens is a multi-element lens, the spacingbetween lens elements can be varied to change the effective radius ofcurvature. Because of the improved beam quality with a spherical lens,the beam radius 3102 with the lens in FIG. 31 b is tighter than the beamradius using a comparable curved mirror configuration, such as 2902 inFIG. 29 b.

Next for the lens system, the focal distance from the mirror versusfiber distance from the mirror 3201 is plotted in FIG. 32, assuming aradius of curvature for the lens of 1.5 mm. By varying the fiberdistance from ˜1.5 mm to 4.5 mm, the focal distance decreases from ˜5.5mm down to above 2.5 mm. Once again, moving the fiber with respect tothe turning mirror leads to a method of adjusting the focal distance.Moreover, for certain focal distances of FIG. 32 (circled points), FIG.33 provide diagrams for the radius of curvature of 1.5 mm. Inparticular, curve 3301 corresponds to 3202, curve 3302 corresponds to3203, and curve 3303 corresponds to 3204. As can be seen, using the lenssystem leads to a much more symmetric beam along the x- and y-axes. Thisis also the reason that a tighter focus beam waist is possible using thelens system.

Although two examples have been provided for turning and focusing thelight delivered by a catheter, there are many other embodiments that canalso be used and are intended to be covered by this disclosure. As anexample, an alternative embodiment may be to use a lens tipped fiberwith or without a turning mirror. For instance, lens-tipped fibers maybe fabricated by using a laser to shape the end of the fiber, or byusing mechanical polishing to create a lens at the end of a fiber. Thelight emerging from the fiber may then be converging, collimated, ordiverging, depending in part on the radius of curvature at the end ofthe fiber. In some cases, the lens tipped fiber may also be coated, suchas when an anti-reflection coating is desired. In one particularembodiment, a lens tipped fiber may be inserted into a catheter and usedto focus light near the end face of the catheter. In this case, thefocal plane may be adjusted by adjusting the lens tipped fiber locationwith respect to the end of the catheter face. In an alternativeembodiment, by moving a lens-tipped fiber with respect to a flat turningmirror, the focal distance can be varied. A lens tipped fiber may becombined with any of the designs for catheters described in thisspecification.

In the design of FIG. 21, to perform therapeutic or diagnosticprocedures on multiple angles requires either rotation of the tip usinga micro-motor 2103 or manual rotation of the catheter. As analternative, a conical shaped reflective surface can be used to turn andfocus multiple spots in an artery. In one embodiment, FIG. 34 shows thecross-section of a cylindrically symmetric catheter probe 3400. Thecurved mirror can be rotated about the cylindrical surface to create apointy conical surface 3401. Then, multiple fiber outputs can be focusedinto different directions. In a particular embodiment, FIG. 34illustrates two fibers 3402 and 3403, although any number of fiberscould be used. In one preferred embodiment to hit four spots on anartery at 90 degree intervals, four fibers could be used placedsymmetrically around the cylinder axis. With these multiple spots, aprocedure at a location in the artery could be performed in the fourorthogonal directions approximately simultaneously. The fibers could beindividual fibers, or they could in a preferred embodiment be a fiberbundle with multiple cores. For individual fibers, the catheter mighthave four holes in a solid cylindrical insert in the catheter to holdthe fibers in place. The catheter can also have a radio opaque tip 3404for guiding into the patient, and windows 3405 could be used forpermitting the light to be passed to the artery wall. One challenge ofsuch a design might be that all the fibers and the conical tip may haveto still fit within a ˜2 to 2.5 mm catheter outer diameter.

In the case of multiple fibers used in the catheter such as in FIG. 34,one or more mid-infrared laser outputs can be used. FIG. 35 illustratesone embodiment where a single mid-infrared laser output is coupled tofour fibers to be fed into the catheter. First, the output of themid-infrared laser may be coupled to a connecter or coupler 3501. Theconnector 3501 may then connect to a demultiplexer 3502 to divide thelaser output into four beams. The demultiplexer 3502 could be a powerdivider, a polarization divider, or a wavelength division demultiplexer,although a power divider would be more appropriate if the same light isto be fed into the four fibers. The output of the demultiplexer 3502 isthen coupled to the fibers to be inserted into the catheter 3504. In onepreferred embodiment, there may be connector or couplers 3503 to connectthe demultiplexer to the catheter fibers, so that the demultiplexer 3502does not have to be replaced each time even if the catheter fibers arereplaced after each use.

In some applications, it may be desirable to have the catheterpositioned approximately near the center of an artery. In addition, itmay be desirable to stop or slow the flow of blood and other fluidsthrough the artery temporarily during the procedure. FIG. 36 shows oneembodiment of a device 3600 for positioning in the center and impedingblood and fluid flow. In this embodiment a balloon 3604, 3605 is placedaround the catheter center 3601, where the balloon can be deflated 3604while passing through the artery, and the balloon can be inflated 3605after the catheter reaches near the location desired in the artery. Asthe expanded balloon 3605 can contact the artery wall 3602, the bloodand fluid flow around the catheter can be impeded. It may be acceptableto impede blood flow for short periods of time during a medicalprocedure. In the example of FIG. 36 the catheter 3601 shown is similarto the design of FIG. 34. One modification may be the addition of apassage 3606 through the catheter, which may have air of fluid forinflating the balloon 3605. Although a particular catheter design with aballoon is shown in FIG. 36, any of the other catheter designs describedin this disclosure may be used as the core region of the catheter.

One limitation of the design in FIG. 36 is that the light from the endof the catheter 3601 has to travel through the radius of the artery, andthen pass through the artery wall, if necessary. The focal length has tobe adjusted for the additional distance, and there may also beadditional loss for the laser light as the beam passes through theradius of the catheter. Another embodiment of a balloon-type catheterthat may overcome this limitation is illustrated in FIGS. 37 and 38. Inthis embodiment 3700, the turn mirror and lens or curved mirror 3704 isseparated into two or more segments, and each segment may be attached orcoupled to the wall of the balloon 3703. As an example, FIG. 37 a showsthe catheter 3701 within the artery wall 3702 when the balloon 3703 isdeflated. This would be the state while the catheter is being insertedinto the patient. As with the other designs, there can be a radio opaquetip 3705 to help guide the catheter into the body using an imagingsystem.

After the catheter is located near the desired location 3750 in theartery wall 3752, then the balloon 3753 may be inflated or expanded. Inone embodiment, air or fluid may be passed through an inflation passage3756 in the catheter. It may be desirable to have the balloon 3753 incontact with the artery wall 3752 to expel blood or fluid between thecurved mirror 3754 and the artery wall 3752. Another advantage of theballoon catheter may be that the catheter end is softer and moreflexible, so the catheter may approach parts of the body or artery witha cushioned contact. The radio opaque tip 3755 may help identify thelocation of the catheter head 3700. For the purpose of illustration,FIG. 37 b uses the curved mirror catheter design. However, any of thecatheter and focusing optics designs described in this specification canbe used within the expanding balloon. The catheter tube 3751 may feed inthe one or more fibers 3757 in addition to possibly the inflationpassage 3756. The curved mirror segments 3754 may be attached to theballoon wall 3753, and as the balloon 3753 is inflated, the curvedmirror segments 3754 expand out like petals on a flower. Although twocurved mirror segments 3754 are illustrated, any number of segments canbe used in such a design. The curved mirror segments 3754 are fed byfibers 3757 that also follow the segments 3754, so that the light can beemitted near the artery wall 3752 at the location of the curved mirrors3754.

A more detailed diagram 3800 of a particular embodiment with the balloon3801 in approximate contact with the artery wall 3805 is shown in FIG.38. The balloon 3801 may be expanded to expel blood or other fluids fromthe interface with the artery wall. As an example, mid-infrared lightmay be coupled through the fiber 3803, and the output light 3804 fromthe fiber may be turned and focused using a curved mirror 3802 that isattached or coupled to the balloon head or wall 3801. The artery wall3805, for instance, may be composed of an endothelium layer 3806, asmooth muscle cell media 3807, and an adventitia layer 3808. In onepreferred embodiment, it may be advantageous to have the focal spot orfocal plane 3809 fall within the adventitia 3808 or even beyond theadventitia. For example, damage to the endothelium 3806 or smooth musclecell media 3807 may be minimized in such a focusing arrangement for atherapeutic procedure. In one embodiment, the damage to the endothelium3806 and at least the top part (closer to the endothelium) of the smoothmuscle cell media 3807 may be reduced or partially minimized because thebeam light intensity is lower in these sections as compared with thedeeper layers such as the adventitia 3808 where the focal spot lies. Inother words, as the beam approaches the focus, the light intensityincreases. As described in other embodiments, the focal distance may beadjusted by changing the curvature of the mirror 3802 or by changing thespacing between the end of the fiber 3803 and the curved mirror 3802.Although illustrated in one particular catheter embodiment, any of theother embodiments described in this specification may also be used withthe petal expansion of the mirrors or lenses within the balloon 3801.

Although particular embodiments for a catheter comprising a fiber orlight pipe have been described, any combination of the elements may beused along with other improvements. As an example of other improvements,it may be desirable to cool the light turning mirrors, or it may bedesirable to use multiple optical elements. For example, in someparticularly therapeutic applications, a significant amount of light maybe incident on the catheter focusing element. Therefore, it may beadvantageous to cool the optics to avoid thermal damage or significantheat generation in the small area. Although air cooling could be used,air cooling may not be as effective if the catheter outer diameter isonly ˜2-2.5 mm. FIG. 39 illustrates several embodiments that may be usedto reduce the heating within the catheter optics. In FIG. 39 a, acatheter 3900 is illustrated with fluid cooling for the curved mirrorstructure. The outer diameter of the catheter is 3901, which alsocomprises a fiber 3902. The curved mirror surface 3904 of thisembodiment has one or more cooling fluid tubes 3903 feeding coolingfluid to and around the mirror 3904 to aid in removing some of the heat.The beam may be focused 3905 outside the catheter, and the cooling fluidtubes 3903 may be positioned to avoid blocking or cutting the lightbeam. In a further embodiment, it may also be desirable to reduce theheating at the curved mirror 3904 by using a metal or dielectric coatingthat substantially minimizes absorption at the light wavelengths. Forexample, if a metal coating is used, then the metal should be selectedto have a high reflectivity at the desired light wavelengths. Forvisible light, the metal coating could be silver, and for infrared lightthe coating could be gold. Alternatively, a single- or multi-layereddielectric coating could be used to substantially minimize absorptionand heating at the mirror 3904.

In an alternate embodiment, the beam size at the catheter optics can bemade larger, for example, to reduce the light intensity and heat densityon the optics. In one example, FIG. 39 b shows a catheter 3930 with atapered fiber 3933 that could be used to expand the beam near the end ofthe catheter fiber 3932. The outer catheter surface is 3931, and thefiber 3932 is pulled to taper out further 3933 before the light exits.This could be accomplished through the fiber fabrication process, postprocessing of the fiber by heating it up and reshaping the fiber, orperhaps by splicing on a multi-mode fiber, grin lens, or just a tube ofglass at the end of the fiber. The beam size on the turning mirror 3934would then be larger, still permitting focusing of the light outside thecatheter outer surface 3931. The end of the tapered fiber 3933 may beangle cleaved or anti-reflection coated to avoid reflection back intothe light source.

In yet another embodiment for reducing the light intensity in thecatheter optics, a large mode area fiber or a multi-mode fiber could beused to deliver the light within the catheter. In the example of FIG. 39c, the catheter 3960 has an outer surface 3961, and the fiber fedthrough the catheter 3962 is a larger core size fiber. As anillustration, it may be advantageous to use the larger core size fiber3962 with an optical design such as described in FIG. 34 with a conicalsymmetry 3963. The multi-mode fiber might have a core diameter of 50,65, 100 or even larger microns, for instance. The higher light densitycould be used to illuminate omni-directionally around the catheter outersurface 3961. The end of the large core area fiber 3964 could also beangle cleaved or anti-reflection coated to minimize retro-reflectioninto the fiber 3962. Although particular examples for cooling the opticsin the catheter have been described for particular types of collimatingor focusing optics, these cooling or expanding techniques could be usedwith any of the optical designs described within this specification.

Many of the examples described thus far involve a single opticalelement, such as a lens or a curved mirror, for collimating or focusingthe light outside the catheter. To provide more flexibility and toreduce the amount of curvature required at the mirror or lens as well asany aberration or distortion penalty, other embodiments may use multipleoptical elements for collimating or focusing the light. In oneparticular embodiment, FIG. 40 illustrates a catheter design 4000 thatuses of a grin (graded index) lens 4003 at the end of the fiber 4002within the catheter outer surface 4001. The grin lens or otherrefractive element may be used to collimate the fiber output or make aslightly diverging beam 4006 onto the curved mirror surface 4004. Thelight output can then pass through a window 4005 on the catheter outersurface 4001 to focus the light at an external focal plane 4007. For theexample of a slightly diverging or focusing beam 4006 after the grinlens 4003, the distance 4008 between the grin lens 4003 and curvedmirror 4004 may be varied to change the distance to the focal plane4007. Although a grin lens 4003 is shown in FIG. 40, a lens, alens-tipped fiber, or any other refractive element may be used.

To illustrate the flexibility gained using multiple optical elements,ZEMAX simulations were also performed for different embodiments usingmultiple elements. In a particular embodiment simulated in FIG. 41, amulti-element optical system 4100 comprises a curved parabolic mirror4102 followed by a lens 4104 of radius of curvature R. For thisparticular simulation it is assumed that the mirror 4102 radius ofcurvature is 2.2 mm. The fiber end 4101 is a distance 4103 away from thecenter of the mirror 4102, and this distance 4103 may be adjustable. Thelens 4104 helps to focus the light in this embodiment to a focal spot4105 that is a distance 4106 from the center of the mirror 4102. Theentire assembly 4100 may advantageously reside within a catheter thatmay have an outer diameter of ˜2-2.5 mm, or any of the other catheterdimensions in this disclosure.

The configuration 4100 of FIG. 41 permits flexibility in adjusting thefocal distance from the center of the mirror 4102 to the focal spot 4105in a number of ways. In one preferred embodiment, the distance 4103 ofthe fiber end 4101 from the curved mirror center 4102 can be varied tochange the focal distance 4106. For example, FIG. 42 illustrates acalculation 4201 of the focal distance from the mirror 4106 versus thefiber distance from the mirror 4103 assuming a radius of curvature ofthe lens R of 3.2 mm (R=20. In this example the focal distance can bevaried from about 5 mm down to more than 2.5 mm by adjusting the fiberdistance from approximately 1.8 to 3.9 mm. In another embodiment, thefocal distance 4106 can be varied by either changing the radius ofcurvature of the parabolic mirror 4102 or the radius of curvature orfocal length of the lens 4104. The curved mirror 4102 could, in oneexample, be varied by using a MEMS mirror or a deformable reflectivesurface. The lens 4104 may be varied by using a fluid filled lens or amulti-element lens with adjustable spacing between the lens.

In yet another embodiment, a multi-element optical catheter design 4300illustrated in FIG. 43 uses two lenses and a flat mirror to turn thebeam by 90 degrees. The fiber end 4301 is assumed for these simulationsto be a distance 4308 of 0.5 mm from the first lens 4302. This firstlens 4302 is a distance 4305 from the center of the flat mirror 4303,and the beam is focused using a second lens 4304 to a focal spot 4307that is a distance 4306 from the center of the flat mirror 4303.Although held fixed here, the distance of the fiber to the first lens4308 could be varied, if desired. Also, although two lenses areillustrated in 4300, any number of lenses could be used and are intendedto be covered by this disclosure.

There are a number of methods of adjusting the focal distance 4306 inthe configuration 4300. For example, FIG. 44 a shows a calculation 4401of the focal distance from the mirror 4306 versus the distance betweenthe first lens and the flat mirror 4305. The focal distance 4306 can bevaried from approximately 5 mm down to 2.8 mm by varying the distancebetween the first lens and the flat mirror 4305 between about 0.5 mm and4.5 mm. In another preferred embodiment, the focal distance 4306 mayalso be varied by changing the distance between the first lens 4302 andthe second lens 4304. For example, FIG. 44 b illustrates a calculation4450 of the change in focal distance from the mirror 4306 versus thedistance between the two lenses. The focal distance can be varied fromabout 5 mm down to 2.8 mm by varying the distance between the two lensesbetween approximately 1.1 mm and 5.25 mm. For both of these simulationsthe fiber is placed 0.5 mm from the first lens, the radius of curvatureof the first lens is assumed to be 1.5 mm, and the radius of curvatureof the second lens is assumed to be 1.6 mm. These values are exemplary,and other values are also intended to be covered by this disclosure.

Different designs of catheters and optical system have been described inthis disclosure. Although particular embodiments are illustrated, thefeatures or parts from different embodiments can be combined ormodified. Also, the output laser light has been illustrated to exitorthogonal to the axis of the catheter and fiber, but any angle of exitof light can be used consistent with the disclosure. The light beamcould be focused, collimated, or even made divergent exiting from thecatheter. Different methods of varying the focal distance to the tissuehave been described including moving the fiber end, changing the radiusof curvature of the mirror or lens, or varying the spacing betweendifferent optical elements. Any combination of these methods could alsobe used to vary the distance from the catheter to the focal spot. Thelight beam coupled to the catheter can be from a light source includinglasers, lamps, light emitting diodes, or another fiber coming from adifferent system. The bandwidth of the light could be narrow or wide,and different wavelength of the light could be in the visible,near-infrared, mid-infrared, or even shorter wavelengths. In onepreferred embodiment, the wavelength of light could be near 1720 nm, sothat the penetration depth into the sample can be about 1 to 1.5 mm ormore because of the local minimum in water absorption and scattering.Also, the 1720 nm window may coincide with absorption peaks in differenttissue, such as lipids, collagen or elastin. Moreover, the catheteroptics can emit the collimated or focused light in one direction, andthen the light can be rotated manually or with a motor, or the lightmight exit in multiple directions using a conical structure withcylindrical symmetry.

Although the present invention has been described in severalembodiments, a myriad of changes, variations, alterations,transformations, and modifications may be suggested to one skilled inthe art, and it is intended that the present disclosure encompass suchchanges, variations, alterations, transformations, and modifications asfalling within the spirit and scope of the appended claims.

What is claimed is:
 1. A system for selectively processing target tissuematerial in a patient, the system comprising: a laser subsystem forgenerating an output laser beam; and a catheter assembly including anoptical fiber having a proximal end coupled to the laser subsystem forguiding the output laser beam along a propagation path, the beam havingoptical and temporal properties and a predetermined selected wavelength,wherein the predetermined selected wavelength is between 1700 nm and1760 nm, the catheter assembly sized to extend through an opening in afirst part of the patient and to a tissue material processing sitewithin the patient, the catheter assembly further including a beamdelivery and focusing subsystem having an adjustable focal distance anddisposed in the propagation path and that accepts the output laser beamand adjustably positions the beam into at least one focused spot on thetarget tissue material disposed within a second part of the patient atthe site based on distance to the target tissue material from apredetermined point on the propagation path at the site for a durationsufficient to allow laser energy to be absorbed by the target tissuematerial and converted to heat to produce a desired physical change inthe target tissue material without causing undesirable changes toadjacent non-target material disposed within the second part of thepatient wherein the target tissue material is characterized by anabsorptive coefficient, and wherein the predetermined wavelength isselected to achieve a penetration depth into the second part of thepatient of approximately one millimeter or more.
 2. The system asclaimed in claim 1, wherein the predetermined wavelength is based on theabsorptive coefficient of the target tissue material, wherein theadjacent non-target material has an absorptive coefficient differentfrom the absorptive coefficient of the target tissue material at thepredetermined wavelength.
 3. The system as claimed in claim 1, whereinthe catheter assembly includes a plurality of optical componentsdisposed along the propagation path.
 4. The system as claimed in claim3, further comprising an actuator for varying distance between a pair ofthe optical components along the propagation path to change the focaldistance.
 5. The system as claimed in claim 4, wherein the pair ofoptical components include a focusing lens and a mirror for bending theoutput laser beam.
 6. The system as claimed in claim 1, wherein thetarget tissue material comprises myelin sheath of at least a part of thenervous system.
 7. The system as claimed in claim 1, wherein the targetmaterial is located within a wall of part of a cardiovascular system atthe target material processing site.
 8. The system as claimed in claim1, wherein the laser beam is a pulsed laser beam, and the pulsed laserbeam has a pulse width shorter than several milliseconds.
 9. An opticalcatheter assembly for use in a system for selectively processing targettissue material in a patient, the assembly comprising: an elongatedflexible housing; an optical fiber disposed in the housing for guidingan output laser beam along a propagation path, the beam having opticaland temporal properties and a predetermined selected wavelength, whereinthe predetermined selected wavelength is between 1700 nm and 1760 nm,the housing sized to extend through an opening in a first part of thepatient and to a tissue material processing site within the patient; anda beam delivery and focusing subsystem having an adjustable focaldistance disposed in the propagation path and that accepts the outputlaser beam and adjustably positions the beam into at least one focusedspot on the target tissue material disposed within a second part of thepatient at the site based on distance to the target tissue material froma predetermined point on the propagation path at the site for a durationsufficient to allow laser energy to be absorbed by the target tissuematerial and converted to heat to produce a desired physical change inthe target tissue material without causing undesirable changes toadjacent non-target material disposed within the second part of thepatient wherein the target tissue material is characterized by anabsorptive coefficient, the predetermined wavelength being based on theabsorptive coefficient of the target tissue material, wherein theadjacent non-target material has an absorptive coefficient differentfrom the absorptive coefficient of the target tissue material at thepredetermined wavelength.
 10. The assembly as claimed in claim 9,wherein the predetermined wavelength is selected to achieve apenetration depth into the second part of the patient of approximatelyone millimeter or more.
 11. The assembly as claimed in claim 9, whereinthe catheter assembly includes a plurality of optical componentsdisposed along the propagation path.
 12. The assembly as claimed inclaim 11, further comprising an actuator for varying distance between apair of the optical components along the propagation path to change thefocal distance.
 13. The assembly as claimed in claim 12, wherein thepair of optical components include a focusing lens and a mirror forbending the output laser beam.
 14. The assembly as claimed in claim 9,wherein the target tissue material comprises myelin sheath of at least apart of the nervous system.
 15. The assembly as claimed in claim 9,wherein the target material is located within a wall of part of acardiovascular system at the target material processing site.
 16. Theassembly as claimed in claim 9, wherein the laser beam is a pulsed laserbeam, and the pulsed laser beam has a pulse width shorter than severalmilliseconds.